Oral contraceptives (OCs) affect the risk of several cancers in women, but have been virtually unstudied for squamous cell carcinoma (SCC). We examined the hypothesis that OCs influence SCC risk in a case–control study among women and also examined whether polymorphisms in the DNA repair gene, Xeroderma pigmentosum group D (XPD), modified the risk. Incident cases of SCC were identified by a network of dermatologists and pathology laboratories. Population-based controls were frequency matched to cases by age and gender (n=261 SCC cases, 298 controls). Overall, OC use was associated with a 60% higher risk of SCC (odds ratio (OR), 1.6; 95% confidence interval (95% CI): 1.0–2.5). ORs for SCC were higher among those who last used OCs ≥25 years before diagnosis (OR: 2.1; 95% CI: 1.2–3.7), and among these women, SCC risk increased with duration of use (OR for ≤2 years, 1.7; 95% CI: 0.9–3.5; OR for 3–6 years, 2.6; 95% CI: 1.0–6.5; OR for ≥7 years, 2.7; 95% CI: 0.9–8.5, P_trend=0.01). Furthermore, the XPD Lys751Gln polymorphism was a significant modifier of the OC-SCC association (P_interaction=0.03). These findings lead us to hypothesize a potential relationship between OCs and SCC risk, and that this could involve DNA repair pathways.