Until recently, chemotherapy for visceral leishmaniasis (VL; also known as kala-azar) was severely limited by factors such as high cost, route of administration, generation of side effects and potential for resistance. Although largely effective, chemotherapies have become available with the introduction of new drugs and multi-drug regimens for VL. These could be further improved by the identification of biomarkers that are altered during effective treatment. The identification of such biomarkers in the circulation would also simplify efficacy trials. In this study, we determined immunological signatures within the serum of ethnically and geographically distinct VL patients (from Bangladesh and Brazil). Our results indicate that inflammatory and regulatory cytokines (IFNγ, TNFα, IL-10, IL-17), as well as levels of growth factors (FGF, VEGF), are elevated within the serum of VL patients from these sites. The examination of samples from Brazilian VL patients during and beyond standard treatment with meglumine antimoniate identified multiple parameters that revert to levels comparable to those of healthy endemic control individuals. The consolidation of these results provides a 'response to treatment' signature that could be used within efficacy trials to rapidly and simply determine successful interruption of VL.