Accumulating evidence had implicated pathological involvement of interleukins (ILs) in progression and complications in patients with type 2 diabetes mellitus (T2DM). Dipeptidyl peptidase-4 inhibitors (DPP-4i) produced favorable effects on glucose homeostasis in T2DM. This study aimed to evaluate the impact of DPP-4i on interleukins (ILs) concentrations in T2DM.PubMed, Embase and the Cochrane library were systematically searched for relevant articles from inception to May 31, 2024. Related searching items were used including DPP-4i, T2DM and randomized controlled trials (RCTs).Placebo- or active agents-controlled human studies were screened. All the RCTs were identified if they provided detailed information on changes of ILs during DPP-4i treatment.A total of 14 RCTs involving 850 participants were identified. Pooled estimates revealed that DPP-4i significantly lower IL-6 concentrations (-0.54 pg/mL, 95% CI, -0.82 to -0.25, I2 = 10%, P = 0.0003) compared to placebo. Similar effects were demonstrated for IL-1β (-16.33 pg/mL, 95% CI, -19.56 to -13.11, I2 = 0%, P<0.00001), whereas the effect on IL-18 was not statistically significant (-13.55 pg/mL, 95% CI, -76.95 to 49.85, I2 = 0%, P = 0.68). Subgroup analysis on IL-6 demonstrated that marked effects were found in groups of basal IL-6 concentrations (< 5 pg/mL), BMI (≥ 28 kg/m2) and type of DPP-4i (linagliptin).DPP-4i favorably decreased concentrations of IL-6 in patients with T2DM. The impact of DPP-4i on IL-1β and IL-18 needed to be explored with more studies. Further trials should be performed to elucidate this anti-inflammatory effect of DPP-4i during treatment of T2DM.© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.