BACKGROUND: The long-term impact of DPP-4 inhibition is unknown and there are concerns about the influence of DPP-4 inhibition on carcinogenesis of the pancreas and thyroid. As DPP-4 is a rather unselective enzyme present in many tissues, we focuseon all specific cancer types. METHODS: PubMed and EMBASE were searched between Jan 2005 and Apr 2017 to identify studies comparing DPP-4 inhibitors with either placebo or active drugs on cancer risk. Studies were included if they reported on at least one specific cancer outcome and had a follow-up of at least one year after start of drug use. Methodological quality of the studies was assessed by the Cochrane Collaboration’s tool and the Newcastle-Ottawa Scale. RESULTS: 25 studies met the inclusion criteria (12 RCTs and 13 observational studies). Sample sizes of the DPP-4 inhibitor groups ranged from 29 to 8,212 patients for RCTs and from 2,422 to 71,137 patients for observational studies. Mean age ranged from 51 to 76 years, mean follow-up was 1.5 years. None of the pooled (sensitivity) analyses, except the observational studies studying breast cancer (HR (95%CI): 0.76 (0.60-0.96)), showed evidence for an association between DPP-4 inhibitors and site-specific cancer. Also for pancreatic and thyroid cancer no statistically significant risk was found. CONCLUSION: Based on the current literature it is not possible to conclude whether DPP-4 inhibitors were associated with an increased risk of site-specific cancer. Future studies should address the methodological limitations and follow patients for a longer period in order to determine the long-term cancer risk of DPP-4 inhibitors.