This study aimed to identify laboratory factors predicting leprosy relapse (LR) after multi-drug therapy (MDT). Acase–control study included 80 patients treated with MDT at a national reference center over 12 years. The RelapseGroup had 40 patients who relapsed after an average of 89.2 months post-MDT, while the Control Group had 40patients who remained asymptomatic for an average of 113.1 months. Significant predictors of LR includedneural/perineural lymphocytic infiltrate (OR = 4.67; p = 0.0076) and foamy granulomas (OR = 15.55; p = 0.0005),increasing odds by 4.7 and 15.6 times, respectively. The Relapse Group had a mean histological bacillary index (hBI)of 3.23+ compared to 1.8 in the Control Group (p = 0.004). An hBI ≥3+ had 72% sensitivity and 65% specificity fordetecting LR (AUC = 0.72; p = 0.0002). Elevated anti-phenolic glycolipid I (anti-PGL-I) IgM antibody levels (ELISAindex, EI ≥1) were also associated with LR (OR = 4.67; p = 0.0031). An EI ≥3.6 had 71% sensitivity and 62% specific-ity (AUC = 0.70; p = 0.0012). Multivariate analysis indicated that neural/perineural infiltrate, foamy granulomas,hBI ≥ 1+, and EI ≥ 1 significantly predicted LR, with up to 94.32% probability. Conclusively, these factors can identifyindividuals at high probability of LR after MDT.(AU).