AIM: To evaluate the efficacy and safety of the intravitreal dexamethasone implant in naive and refractory patients with diabetic macular edema (DME). METHODS: PubMed, Embase, Web of Science, and Medline databases were searched. The main outcomes were best-corrected visual acuity (BCVA) and central retinal thickness (CRT). The secondary outcomes included mean number of injections, intraoperative or postoperative complications including intraocular pressure (IOP) elevation and cataract. RESULTS: Ten comparative studies involving a total of 1000 DME eyes including 402 naive eyes and 598 refractory eyes were selected. The postoperative BCVA in the naive group was significantly better than in the refractory group [mean difference (MD) -0.11, 95% confidence interval (CI) -0.17 to -0.05, P=0.0003; MD 8.69, 95%CI 5.08 to 12.30, P<0.00001)]. Additionally, the naive group got greater improvement of BCVA change as well as more gains of BCVA letters than the refractory group [MD 7.71, 95%CI 2.02 to 13.40, P=0.008; odds ratio (OR) 2.99, 95%CI 2.05 to 4.37, P<0.00001]. The subgroup analysis revealed that the naive group had significantly higher BCVA gains of ≥5, ≥10, and ≥15 letters compared to the refractory group (P=0.002, 0.0001, 0.003, respectively). No significant difference was detected between the two groups in either postoperative CRT (MD -22.36, 95%CI -46.39 to 1.66, P=0.07) or the overall mean number of injections (MD -0.08, 95%CI -0.38 to 0.22, P=0.61). Intraoperative and postoperative complications including the elevation of IOP (OR 0.47, 95%CI 0.20 to 1.13, P=0.09) and cataract (OR 1.78, 95%CI 0.97 to 3.24, P=0.06) showed no significant differences between the two groups during the follow-up time. CONCLUSION: Intravitreal dexamethasone implants for DME can improve anatomical and functional outcomes in both naive and refractory eyes and have a well-acceptable safety profile. Moreover, naive eyes maintain better visual outcomes than refractory eyes. It provides further evidence of better visual response when used for naive eyes as first-line therapy.