Objective: To determine the incidence of cutaneous squamous cell carcinoma (SCC) in patients with rheumatoid arthritis receiving etanercept, a tumor necrosis factor antagonist, for up to 5 years. Design: An etanercept clinical trials' database and an etanercept postmarketing surveillance database were retrospectively analyzed for the incidence of SCC. Setting: Patients enrolled in clinical trials of etanercept were from private and institutional practices. The postmarketing database comprised reports from postmarketing trials and solicited and spontaneous reports. Patients: A total of 1442 patients with rheumatoid arthritis with 4257 patient-years of etanercept exposure (median exposure, 3.7 years) are included in the clinical trials' database. More than 125 000 patients with more than 250 000 patient-years of etanercept exposure are included in the etanercept postmarketing database. Interventions: Most patients enrolled in clinical trials of etanercept received a dosage of 25 mg of etanercept subcutaneously twice weekly for most of the time they received etanercept therapy. Results: Only 4 cases of SCC were observed in the etanercept clinical trials' database, an incidence that compares favorably with the expected incidences based on general population data from Arizona (13.1) and Minnesota (5.9). Similarly, few cases of SCC (1 per 10 000 patient-years) have been reported during postmarketing surveillance of etanercept therapy. Conclusion: In patients with rheumatoid arthritis, etanercept use of up to 5 years does not seem to be associated with an increase in the incidence of cutaneous SCC.