Abstract Vitiligo is a common, acquired depigmenting skin disease. There have been concerns that vitiligo and its treatment may increase the risks of skin cancer. In a large UK population-based study, we aimed to establish whether vitiligo is associated with an increased risk of skin cancer. We used routinely collected electronic medical records of adults contributing to the Optimum Patient Care Research Database (2010–2020). Cases of vitiligo were identified using specific diagnosis codes. Those with other depigmenting conditions were excluded. Vitiligo cases were age and sex matched with up to four controls registered at the same general practice and with at least one primary care interaction in the preceding year. The primary outcome was risk of skin cancer; comprisied of melanoma, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). Individual skin cancers and actinic keratoses (AK) were included as secondary outcomes. Associations between vitiligo and skin cancer were estimated using Cox regression, with adjustment for age, sex, socioeconomic deprivation, ethnicity, body mass index, smoking and alcohol status, immunotherapy, phototherapy and 13 common comorbidities. Prespecified subgroup analysis comprised stratification by sex, age group (18–45 years, 45–65 years and > 65 years), ethnicity (White and non-White) and socioeconomic deprivation. In total, 14 976 patients with vitiligo were matched to 54 392 controls. Over the 10-year study period, 133 patients with vitiligo and 783 controls developed new-onset skin cancer. Vitiligo was associated with a 38% reduced risk of any new-onset skin cancer [adjusted hazard ratio (aHR) 0.62, 95% confidence interval (CI) 0.51–0.74; P < 0.001]. This risk reduction was observed for all individual skin cancer types: melanoma (aHR 0.38, 95% CI 0.23–0.64; P < 0.001), SCC (aHR 0.65, 95% CI 0.48–0.87; P = 0.004), BCC (aHR 0.65, 95% CI 0.51–0.83; P < 0.001) and AK (aHR 0.86, 95% CI 0.75–0.98; P = 0.028). In a subgroup analysis, vitiligo was associated with a reduction in skin cancer risk in people identifying as White (aHR 0.68, 95% CI 0.55–0.84; P < 0.001), but there was no association in those identifying as non-White (aHR 0.93, 95% CI 0.44–1.98). Vitiligo-associated reductions in skin cancer risk were consistently observed in the other prespecified subgroups. Vitiligo is associated with a strong protective effect against common types of skin cancer. Vitiligo-associated risk reduction is most marked for melanoma (62% lower risk). Protective effects associated with vitiligo may be restricted to people with light skin, although skin cancers in the those with darker skin were uncommon, which requires further study. FundingThis research was sponsored by Pfizer. Medical writing and statistical support was provided by Momentum Data and was funded by Pfizer.