BACKGROUND: The treatment of chronic hypersensitivity pneumonitis (cHP) often includes systemic oral corticosteroids, but the optimal pharmacologic management remains unclear. The morbidity associated with prednisone has motivated the search for alternative therapies. We aimed to determine the effect of treatment with mycophenolate mofetil (MMF) or azathioprine (AZA) on lung function in patients with cHP. METHODS: Patients with cHP treated with either MMF or AZA were retrospectively identified from four interstitial lung disease centers. Change in lung function before and after treatment initiation was analyzed using linear mixed-effects modeling (LMM), adjusting for age, sex, smoking history, and prednisone use. RESULTS: Seventy patients were included: 51 were treated withMMFand 19 with AZA. Median follow-up after treatment initiation was 11 months. Prior to treatment initiation, FVC and diffusion capacity of the lung for carbon monoxide (DLCO)% predicted were declining at amean rate of 0.12% (P <.001) and 0.10% (P <.001) per month, respectively. Treatment with either MMF or AZA was not associated with improved FVC (0.5% at 1 year; P =.46) but was associated with a statistically significant improvement in DLCO of 4.2% (P <.001) after 1 year oF treatment. Results were similar in the subgroup of patients treated with MMF for 1 year; the FVC increased nonsignificantly by 1.3% (P =.103) and DLCO increased by 3.9% (P <.001). CONCLUSIONS: Treatment with MMF or AZA is associated with improvements in DLCO in patients with cHP. Prospective randomized trials are needed to validate their effectiveness for cHP.