To evaluate the efficacy and safety of the intravitreal dexamethasone implant in naive and refractory patients with diabetic macular edema (DME). 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. 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. 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.