PURPOSE: Inhibitors of the mammalian target of rapamycin (mTOR) kinase have shown clinical activity in several lymphoma subtypes. Sirolimus, an mTOR inhibitor, also has activity in the treatment and prophylaxis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem-cell transplantation (HSCT). We hypothesized that the use of sirolimus for GVHD prophylaxis in patients with lymphoma might lead to improved survival after transplantation through a decreased incidence of disease progression. PATIENTS AND METHODS: We retrospectively analyzed 190 patients who underwent transplantation for lymphoma. We compared the outcomes of patients who received sirolimus for GVHD prophylaxis with those of patients who received transplantation with a combination of a calcineurin inhibitor and methotrexate without sirolimus. RESULTS: Overall survival (OS) after transplantation was significantly superior in the sirolimus group, which was confirmed in multivariable analysis. The benefit was restricted to patients undergoing reduced-intensity conditioning (RIC) HSCT (3-year OS, 66% for sirolimus group v 38% for no-sirolimus group; P = .007; hazard ratio [HR] for mortality in multivariable analysis = 0.5, P = .042). Patients who received sirolimus had a similar incidence of nonrelapse mortality but a decreased incidence of disease progression compared with patients who did not receive sirolimus (3-year cumulative incidence of progression, 42% v 74%, respectively; P < .001; HR for progression in multivariable analysis = 0.4, P = .01). The effect of sirolimus persisted after adjusting for the occurrence of GVHD. No such survival advantage was apparent in a similar comparison of patients who underwent transplantation for diseases other than lymphoma. CONCLUSION: This study suggests that sirolimus can independently decrease the risk of lymphoma progression after RIC HSCT, paving the way for prospective clinical trials.