To examine the outcomes of dipeptidyl peptidase-4 (DPP-4) inhibitor initiation with and without concurrent metformin treatment.We identified Medicare enrollees initiating a DPP-4 inhibitor, a sulphonylurea or a thiazolidinedione. Using propensity-score-weighted Poisson models, we evaluated 1-year cardiovascular (CV) outcome incidence among initiators of DPP-4 inhibitors versus comparators in subgroups with and without concurrent metformin use, and assessed the interaction between initiation drug and metformin. Outcomes included mortality, non-fatal myocardial infarction (MI), stroke, and a composite outcome.For the DPP-4 inhibitor (n = 13 391) versus sulphonylurea (n = 33 206) comparison, rate differences in composite outcome incidence favoured DPP-4 inhibitors: -2.0/100 person-years among metformin users (95% confidence interval [CI] -2.7 to -1.3) and - 1.0/100 person-years (95% CI -1.8 to -0.2) among metformin non-users. Similar rate difference trends among metformin users and non-users were seen for mortality (-1.5/100 person-years [95% CI -2.1 to -0.9] and -0.7/100 person-years [95% CI -1.4 to 0.0]) and non-fatal MI (-0.5/100 person-years [95% CI -0.8, -0.3] and 0.1/100 person-years [95% CI -0.2 to 0.4]). The interaction between DPP-4 inhibitor initiation and metformin was statistically significant for non-fatal MI (P = 0.008). For the DPP-4 inhibitor (n = 22 210) versus thiazolidinedione (n = 9517) comparison, rate differences in composite outcome incidence for DPP-4 inhibitor initiation were -0.6/100 person-years (95% CI -1.5 to 0.2) among metformin users and 1.0 (95% CI 0.0 to 2.0) among metformin non-users. Similar rate difference trends among metformin users and non-users were seen for mortality (-0.5/100 person-years [95% CI -1.3 to 0.1] and 0.8/100 person-years [95% CI -0.0 to 1.7]) and non-fatal MI (-0.1/100 person-years [95% CI -0.4 to 0.2] and 0.2/100 person-years [95% CI -0.1 to 0.6]). The interaction between DPP-4 inhibitor initiation and metformin was statistically significant for the composite outcome (P = 0.024) and mortality (P = 0.023).Incidence rate differences in multiple CV outcomes appeared more favourable when DPP-4 inhibitor initiation occurred in the presence of metformin, suggesting a possible interaction between DPP-4 inhibitors and metformin.