Little is known about the use of sirolimus for primary prevention of cutaneous squamous cell carcinoma (SCC) among solid organ transplant recipients (SOTRs). We examined the association between sirolimus exposure and incident SCC risk among SOTRs within Kaiser Permanente Northern California. Using a retrospective cohort of all Kaiser Permanente Northern California members given a diagnosis of SOTR from 2000 through 2010, we evaluated incident posttransplantation SCC risk in relation to sirolimus exposure. Sirolimus use was determined from electronic pharmacy records, and incident posttransplantation SCCs were identified from health plan electronic pathology records. We used extended Cox regression to examine the independent association between receipt of sirolimus and risk of SCC. Among 3539 SOTRs, 488 were exposed to sirolimus and 47 developed an incident SCC. SCC risk was not associated with ever use of sirolimus (adjusted hazard ratio 1.18, 95% confidence interval 0.84-1.16) or cumulative duration of sirolimus exposure (adjusted hazard ratio 2.75, 95% confidence interval 0.84-9.04, comparing long-term users with nonusers). No information was available for some known SCC risk factors, such as skin type and sun exposure. Among a large cohort of SOTRs, sirolimus exposure was not associated with a reduction in incident posttransplantation SCC risk.