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Background: Isotretinoin is the drug of choice for severe acne. We sought to examine the potential link between isotretinoin and insulin resistance., Methods: We conducted a systematic review and meta-analysis in accordance with the PRISMA statement. A comprehensive search of the PubMed/MEDLINE, SCOPUS, and Cochrane databases was performed until 12 January 2022 utilizing the PICO (Patient, Intervention, Comparison, Outcome) tool. Fifteen English-language studies focusing on isotretinoin-treated acne patients were included. Serum levels of insulin, glucose, and adiponectin were evaluated before and after treatment, and insulin sensitivity was assessed using the HOMA-IR. A meta-analysis was conducted using RevMan 5.4.1 software, and a quality assessment was undertaken using the ROBINS-I tool., Results: The meta-analysis unveiled a statistically significant rise in the post-treatment levels of adiponectin, an anti-inflammatory agent, which inhibits liver glucose production while enhancing insulin sensitivity (SMD = 0.86; 95% confidence interval (95% CI) = 0.48-1.25, p -value < 0.0001; I 2 = 58%). Our subgroup analysis based on study type yielded consistent findings. However, no statistically significant outcomes were observed for insulin, glucose levels, and the HOMA-IR., Conclusions: There is not a clear association between isotretinoin and insulin resistance, but it appears to enhance the serum levels of adiponectin, which participates in glucose metabolism.