Aims: Medication adherence and persistence are important determinants of treatment success in type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis evaluated the real-world adherence, persistence, and in-class switching among patients with T2DM prescribed dipeptidyl peptidase-4 (DPP4) inhibitors. Methods: MEDLINE, EMBASE, Cochrane Library, PsychINFO, and CINAHL were searched for relevant observational studies published in the English language up to 20 December 2019. This was supplemented by manual screening of the references of included papers. Random-effects meta-analysis was performed. Results: Thirty-four cohort studies involving 594,138 patients with T2DM prescribed DPP4 inhibitors from ten countries were included. The pooled proportion adherent (proportion of days covered (PDC) or medication possession ratio (MPR) ≥ 0.80) was 56.9% (95% confidence interval [CI] 49.3–64.4) at one year and 44.2% (95% CI 36.4–52.1) at two years. The proportion persistent with treatment decreased from 75.6% (95% CI 71.5–79.5) at six months to 52.8% (95% CI 51.6–59.8) at two years. No significant differences in adherence and persistence were observed between individual DPP4 inhibitors. At one year, just 3.2% (95% CI 3.1–3.3) of patients switched from one DPP4 inhibitor to another. Switching from saxagliptin and alogliptin to others was commonest. Conclusions: Adherence to and persistence with DPP4 inhibitors is suboptimal but similar across all medications within the class. While in-class switching is uncommon, saxagliptin and alogliptin are the DPP4 inhibitors most commonly switched. Interventions to improve treatment adherence and persistence among patients with T2DM prescribed DPP4 inhibitors may be warranted.