Background. Treatment for cutaneous leishmaniasis (CL) with standard pentavalent antimonial therapy is hampered by cumbersome administration, toxicity, and potential failure. Knowledge of factors influencing treatment outcome is essential for successful management. Methods. A case-control study of incident cases was performed with patients experiencing their first CL episode. The standard treatment for CL for these patients was 20 mg/kg/day of sodium stibogluconate for 20 days. Clinical and epidemiological data were recorded, and parasite isolates were species typed. Patients were followed up for 6 months to assess treatment outcome. Clinical cure was defined as complete wound closure and re-epithelization without inflammation or infiltration; new lesions, wound reopening, or signs of activity were classified as treatment failure. Descriptive, bivariate, and logistic regression analyses were performed. Results. One hundred twenty-seven patients were recruited; 63 (49.6%) were infected with Leishmania (Viannia) peruviana, 29 (22.8%) were infected with Leishmania (Viannia) braziliensis, 27 (21.3%) were infected with Leishmania (Viannia) guyanensis, and 8 (6.3%) were infected with other species. Only patients infected with the 3 most common species were selected for risk-factor analysis (n = 119). Final failure rate at 6 months was 24.4% (95% confidence interval [CI], 16.5%-32.1%), with 96% of failures occurring within the first 3 months of follow-up assessment. Risk factors for treatment failure identified in the final multivariate model were age (per year, odds ratio [OR], 0.95; 95% CI, 0.92-0.99; P = .017), stay of <72 months in area of disease acquisition (OR, 30.45; 95% CI, 2.38-389.25; P = .009), duration of disease <5 weeks (OR, 4.39; 95% CI, 1.12-17.23; P = .034), additional lesion (per lesion, OR, 2.06; 95% CI, 1.3-3.28; P = .002), infection with L. (V.) peruviana (OR, 9.85; 95% CI, 1.01-95.65; P = .049), and infection with L. (V.) braziliensis (OR, 22.36; 95% CI, 1.89-263.96; P = .014). Conclusions. The identification of parasite species and clinical risk factors for antimonial treatment failure should lead to an improved management of CL in patients in Peru. © 2007 by the Infectious Diseases Society of America. All rights reserved.