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Background: Visceral leishmaniasis (VL) is a life-threatening protozoan disease prevalent in tropical and subtropical regions and a frequent coinfection among people living with HIV. Early identification of patients at high risk of death may reduce case-fatality. This study evaluated the post-test prognostic value of C-reactive protein (CRP) and interleukin-6 (IL-6) as biomarkers of mortality in VL. Methods: A retrospective hospital-based cohort of 101 VL patients was analyzed. CRP and IL-6 concentrations at admission were correlated with clinical findings, the Kala-Cal® prognostic score, and in-hospital mortality. Results: Eight patients died, most presenting with hemorrhagic manifestations. At admission, 87.1% of patients had both biomarkers above the predefined cut-offs. CRP and IL-6 levels were markedly elevated in patients with hemorrhage or fatal outcomes. The AUC was 0.85 for CRP and 0.87 for IL-6, with no significant difference between markers. Optimal prognostic cut-offs were 150 mg/L for CRP and 90 pg/mL for IL-6. Conclusions: In this sample, CRP and IL-6 showed good prognostic performance in VL. In patients with low initial clinical risk, positive biomarker results substantially increased the probability of death. When combined with Kala-Cal®, these markers may improve risk stratification and guide referral decisions.