For patients with idiopathic pulmonary fibrosis, the introduction of new therapies has created an urgent need for better metrics that can help both diagnose the disease and quantify progression or therapy response. This need is well addressed by the chemical shifts and solubility of ¹²⁹Xe in tissues, which have enabled sensitive and direct spectroscopic assessment of lung function¹. Previous work in this arena had recognized only 2 dissolved-phase ¹²⁹Xe resonances associated with barrier tissues and blood. Here we employ improved non-linear curve fitting methods to accurately decompose the complex ¹²⁹Xe FIDs into 3 stable dissolved-phase resonances² in both healthy and IPF subjects. Moreover, we use a more robust gas-phase reference³ to report on frequency shifts and linewidth changes in IPF. By accurately characterizing these spectral differences between healthy and IPF subjects, we can develop quantitative tools that better stage disease progression, assess therapy response earlier, and perhaps even stratify subclasses of IPF to improve outcomes.¹²⁹Xe spectra were acquired from 7 healthy normal (age 38±16.9 years) and 8 IPF subjects (age 65.1±4.9 years) during a 15 second breathold using a 1.5T GE 15M4 EXCITE MRI scanner (GE Healthcare, Waukesha WI) and a Quadrature ¹²⁹Xe vest coil (Clinical MR Solutions, Brookfield, WI). Approximately 200 mL of isotopically enriched ¹²⁹Xe (85%) was hyperpolarized to ~20% via spin-exchange optical pumping (Model 9800, Polarean, Inc., Durham, NC), then combined with 800 mL of N₂. After inhaling the 1 L mixture, 200 FIDs were acquired with the following scan parameters: 512 samples/FID, TE/TR = 0.875/20 ms, BW = 8.06 kHz, 1200 μs 3-lobe sinc pulse, flip angle ≈ ~18°. The first 100 frames were discarded to eliminate contamination from magnetization that originated downstream of the capillary beds. The remaining 100 frames were averaged and then decomposed into a series of exponentially decaying FIDs using the trust-region-reflect algorithm to minimize the complex least-squares residual error⁴. Resonant frequencies were aligned relative to the alveolar gas-phase resonance, which occurs at -2.9 ppm after correcting for the Xe-O² , Xe -Xe, and bulk magnetic susceptibility shifts^5,6,7. Figure 1 illustrates several of the primary differences in ¹²⁹Xe spectra from healthy subjects and patients with IPF. These include readily apparent differences in amplitudes, frequencies, and linewidths of the RBC and 2 barrier peaks. Figure 2 shows that the RBC:barrier continues to be significantly reduced in IPF as found with previous 2-peak fits¹. However, RBC:barrier in healthy subjects is found to be 0.44±0.23 with the 3-peak fit versus 0.55±0.13 with 2-dissolved phase peaks. Figure 3 summarizes the results of two-sample unpaired T-tests of all fit parameters. In IPF patients, the RBC frequency shifts negatively relative to healthy subjects. However, now decomposing the 2 barrier peaks reveals that they also are shifted to lower frequency in IPF. Moreover, in IPF the linewidths of both barrier peaks were found to be dramatically narrower than in healthy volunteers. Finally, phasing the spectra relative to the RBC resonances demonstrated that barrier 1 experiences a statistically different starting phase between IPF and healthy subjects. The reduction in RBC:Barrier among IPF subjects agrees with previous work. However, fitting 2 barrier peaks has reduced the mean RBC:Barrier ratio in healthy subjects. This is reasonable considering that in pure blood consisting of 40% RBC and 60% plasma, the maximum RBC:barrier would be 0.67, even before considering additional barrier components from tissue matrix needed to support the lung. The negative shift of the RBC compartment in IPF is consistent with decreased oxygenation relative to healthy subjects⁸. However, the negative shifts of the two barrier peaks are new compared to previous human studies¹. This difference is likely a consequence of our improved spectral fitting, which also accounts for different phases of the 2 barrier peaks. Both barrier peaks exhibit strikingly narrower linewidths, suggestive of decreased exchange that could result from interstitial thickening physically separating these two compartments. In summary, fitting of the complex ¹²⁹Xe gas exchange spectra to include 3 dissolved-phase resonances reveals numerous spectral parameters that are significantly altered in IPF and may help in both diagnosing and staging this disease.