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There are limited data on the risk of non-melanoma skin cancer (NMSC) and melanoma skin cancer (MSC) among thiopurine-treated patients with ulcerative colitis (UC). Our aim was to investigate the risk while on, by cumulative years, and after stopping thiopurine therapy.Nationwide data were obtained from the Veterans Affairs (VA) health-care system during 2001–2011. We performed a retrospective cohort study evaluating patients with UC. Cox regression was used to investigate the association between thiopurines use and time to NMSC while adjusting for demographics, ultraviolet radiation exposure, and VA visiting frequency. A matched nested case–control study was conducted to investigate the association between thiopurine use and MSC.We included 14,527 patients with UC in the analysis, with a median follow-up of 8.1 years. A total of 3,346 (23%) patients used thiopurines for a median duration of 1.6 years. We identified 421 NMSC and 45 MSC cases. The adjusted hazard ratios of developing NMSC while on and after stopping thiopurines were 2.1 (P<0.0001) and 0.7 (P=0.07), respectively, as compared with unexposed patients. The incidence rate of NMSC among those who never used thiopurines was 3.7 compared with 5.8, 7.9, 8.3, 7.8, and 13.6 per 1,000 person-years for the 1st, 2nd, 3th, 4th, and 5th year of thiopurine use, respectively. No statistically significant association was observed between thiopurine use and MSC, odds ratio 0.8 (P=0.6).In this predominantly white male nationwide cohort, there was a twofold increase in the risk of NMSC while on thiopurines. The incidence rate of NMSC significantly increased with subsequent years of cumulative exposure to thiopurines. Stopping thiopurines reduced the risk of NMSC to pre-exposure levels irrespective of the prior exposure duration.