Sirolimus-associated interstitial pneumonitis is a severe side effect of sirolimus therapy; fatal outcomes have been described. We report 4 patients with sirolimus-associated interstitial pneumonitis and review the literature for risk factors for the development of disease. Until June 2005, 48 patients received either de novo sirolimus treatment (n = 7) or were switched from a calcineurin inhibitor-containing regimen to a sirolimus-based protocol for various indications (n = 41). Compared with the 44 patients on sirolimus therapy with no evidence of a disorder, the 4 patients (8.3%) who developed suspected sirolimus-associated interstitial pneumonitis showed no difference in gender, immunosuppressive therapy, days posttransplantation, comorbidity, or preexistent lung disease. Several points, however, are of interest. None of the de novo-treated patients except 4 patients (9.8%) with late administration of sirolimus developed interstitial pneumonitis. The 4 patients with interstitial pneumonitis tended to be older (58.7 +/- 5.5 vs 46.9 +/- 1.7 years) and received higher sirolimus doses (3.5 +/- 0.5 vs 1.4 +/- 0.2 mg/d) with greater trough levels (15.4 +/- 2.9 vs 8.0 +/- 1.2 micro g/L) at the onset of symptoms. Most notably, all patients with interstitial pneumonitis had a loading dose at the start of therapy, and an increase in sirolimus dose (or trough level) within 3 weeks prior to the onset of symptoms. Additional potential risk factors identified from the literature include allograft dysfunction, hypervolemia, and male gender. With careful monitoring (or even exclusion from therapy) of patients at risk for the development of disease, we have had no case of sirolimus-associated interstitial pneumonitis since September 2004.