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AbstractIntroduction Isotretinoin is a widely used, effective medication for moderate to severe acne. It is typically used for several months, which necessitates regular laboratory monitoring. However, consensus on the optimal assessment frequency is lacking.Method This is a single-center retrospective study on 1182 patients who received isotretinoin for acne at the Dermatology Clinic in Jordan University Hospital over 5 years.Results Of the 1182 patients, 892 (76.57% females) met the inclusion criteria. An increase in the proportion of patients with abnormal triglycerides and total cholesterol levels from baseline to the sixth month was observed (p < 0.05). Conversely, differences in the number of patients with abnormal AST, ALT, and CBC were not found throughout treatment (p > 0.05). Moreover, there was a decrease in the neutrophil-to-lymphocyte ratio (NLR) ratio and systemic inflammatory index (SII) after the sixth month of isotretinoin treatment compared to the baseline (p = 0.012 and p = 0.021, respectively).Conclusions We found that a baseline cholesterol level of 163.9 mg/dl and a baseline triglycerides level of 85.5 mg/dL are highly specific and sensitive in detecting grade 1 abnormalities at the one-month follow-up. This novel prediction approach serves as an effective risk stratification method for isotretinoin acne patients.