BACKGROUND: Laboratory and epidemiologic studies suggest that certain dietary supplements may alter risk of cutaneous squamous cell carcinoma (SCC). OBJECTIVE: We sought to examine the association between supplement use and SCC risk. METHODS: Cases (n = 415) were defined as Kaiser Permanente Northern California members with a pathology-verified SCC in 2004 and control subjects (n = 415) were age-, sex-, and race-matched members with no history of skin cancer. Supplement use and SCC risk factors were ascertained by questionnaire. Associations of SCC with use of multivitamins; vitamins A, C, D, and E; and grape seed extract were estimated as odds ratios and 95% confidence intervals using conditional logistic regression. Models were adjusted for SCC risk factors and other supplement use. RESULTS: Grape seed extract users had a significantly decreased risk of cutaneous SCC (adjusted odds ratio 0.26, confidence interval 0.08-0.89, P = .031). Multivitamin use was associated with a borderline significant reduction in SCC risk (adjusted odds ratio 0.71, confidence interval 0.51-1.00, P = .049). Use of vitamins A, C, D, and E was not associated with SCC risk. LIMITATIONS: The data may be prone to recall and selection bias because of the case-control design. No information was obtained on dose or duration of supplement use. CONCLUSIONS: Use of grape seed extract may be associated with a decreased risk of cutaneous SCC. The other supplements included in our study did not reveal clear associations with SCC risk.