ABSTRACT: Background In patients with post-acute COVID-19-syndrome (PACS), abnormal gas-transfer and pulmonary vascular density have been reported, but such findings have not been related to each other, or to symptoms and exercise limitation. The pathophysiological drivers of PACS in ever- and never-hospitalized patients are not well-understood. Purpose To determine the relationship of persistent symptoms and exercise limitation with 129Xe MRI and CT pulmonary vascular measurements in individuals with PACS. Materials and Methods In this prospective study, patients with PACS aged 18-80 years with a positive PCR COVID test were recruited from a quaternary-care COVID-19 clinic between April and October 2021. Participants with PACS underwent spirometry, diffusing-capacity-of-the-lung- for-carbon-monoxide (DLco), 129Xe MRI, and chest CT. Healthy controls had no prior history of COVID-19 underwent spirometry, DLco, and 129Xe MRI. The 129Xe MRI red-blood-cell (RBC) to alveolar-barrier signal ratio, RBC area-under-the-curve (AUC), CT volume-of-pulmonary-vessels with cross-sectional-area <5mm2 (BV5), and total-blood-volume (TBV) were quantified. St. George's Respiratory Questionnaire (SGRQ), International Physical Activity Questionnaire (IPAQ) and modified Borg Dyspnea Scale (mBDS) measured quality-of-life, exercise limitation and dyspnea. Differences between groups were compared using Welch's T-tests or Welch's ANOVA. Relationships were evaluated using Pearson (r) and Spearman (ρ) correlations. Results Forty participants were evaluated including six controls (mean age, 35±15 years[standard deviation], 3 women) and 34 participants with PACS (mean age, 53±13 years[SD], 18 women), of which 22 were never-hospitalized. The 129Xe MRI RBC:barrier ratio was lower in ever- hospitalized participants (P=.04) compared to controls. BV5 correlated with RBC AUC (ρ=.44,P=.03). The 129Xe MRI RBC:barrier ratio was related to DLco (r=.57,P=.002) and FEV1 (ρ=.35,P=.03); RBC AUC was related to dyspnea (ρ=-.35,P=.04) and IPAQ score (ρ=.45,P=.02). Conclusion 129Xe MRI measurements were lower in ever- hospitalized participants with post- acute COVID-19-syndrome, 34±25 weeks post-infection compared to controls. 129Xe MRI measures were associated with CT pulmonary vascular density, DLco, exercise capacity, and dyspnea. ClinicalTrials.gov: NCT04584671 See also the editorial by Wild and Collier.