OBJECTIVES: To examine the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of heart failure or hospitalization for heart failure in patients with type 2 diabetes. METHODS: We searched Medline, Embase, CENTRAL and ClinicalTrials.gov to identify randomized controlled trials (RCTs) and non-randomized studies of adults with type 2 diabetes that compared DPP-4 inhibitors against placebo or active anti-diabetic medications, and explicitly reported the outcome of heart failure or hospitalization for heart failure. Paired reviewers independently screened for eligible studies, assessed risk of bias, and extracted data. Data from trials and observational studies were pooled separately; quality of evidence was assessed by the GRADE approach. RESULTS: A total of 55 studies involving 1,846,133 patients were eligible, including 43 RCTs (n=68,775) and 12 observational studies (nine cohort studies, and three nested case-control studies; n=1,777,358). There was low-quality evidence regarding risk of heart failure between DPP-4 inhibitor use versus control (38 trials, odds ratio (OR) 0.97, 95% confidence interval (95% CI) 0.61 to 1.56); risk difference 2 fewer (95% CI 19 fewer to 28 more) events per 1000 patients over five years). There was moderate-quality evidence for an increased risk of hospital admission for heart failure in patients treated with DPP-4 inhibitors versus control (five trials, OR 1.13, 95% CI 1.00 to 1.26; RD 8 more (0 more to 16 more)). The observational studies provided effect estimates generally consistent with trial findings, but with very low-quality evidence. CONCLUSIONS: The relative effect of DPP-4 inhibitors on the risk of heart failure is uncertain, given the relatively short follow up and low quality of evidence. Both RCTs and observational studies, however, suggest that these drugs may increase the risk of hospitalization for heart failure in type 2 diabetes patients with existing cardiovascular diseases or multiple risk factors for vascular diseases relative to no use.