Background and objective:  We evaluated the efficacy and safety of everolimus, a macrocyclic proliferation signal inhibitor with anti‐fibroproliferative activity to prevent disease progression or death in patients with IPF, a progressive, fatal disease with no known effective therapy.

Methods:  Eighty‐nine patients with surgical lung biopsy confirmed IPF were enrolled in a 3‐year investigator‐driven, placebo‐controlled, double‐blinded, multicentre study of everolimus.

Results:  The everolimus (n = 44) and placebo (n = 45) groups were matched for demographic variables (gender, P = 0.46) and baseline lung function parameters (FVC, P = 0.29; TLC, P = 0.45; DL_CO, P = 0.41 and PaO₂, P = 0.34). Independent risks for disease progression were everolimus (hazard ratio (HR) 2.37, 95% CI: 1.40–4.00, P < 0.01, log rank) and male gender (HR 2.76, 95% CI: 1.47–5.17, P < 0.01, log rank). Three‐year transplant‐free survival was 36 ± 7% (everolimus) versus 51 ± 8% (placebo) (Kaplan–Meier, P = 0.11, log rank). Independent risks for transplant‐free survival were male gender (HR 2.33, 95% CI: 1.07–5.05, P = 0.03, log rank) and baseline DL_CO (% predicted) (HR 0.96, 95% CI: 0.93–0.99, P = 0.02, log rank).

Conclusions:  Everolimus use was associated with more rapid disease progression in a well‐defined cohort of patients with IPF confirmed by surgical lung biopsy followed for 3 years.