Leishmania is an intracellular protozoan parasite and the etiological agent of a vector-borne disease known as leishmaniasis. This neglected tropical disease exhibits high morbidity and mortality. It is endemic in 97 countries and 700.000–1.000.000 new cases are estimated to occur each year. Leishmania-HIV co-infection has been an emergent public health problem in the last twenty years and has been reported in 35 endemic countries. HIV-infected people are especially vulnerable to visceral leishmaniasis (VL), and VL accelerates HIV replication and advancement to AIDS. In the context of HIV co-infection, the challenges associated with VL disease management are very significant. Disease presentation is often atypical and therapeutical responses are limited with recurrent relapses. A better understanding of the disease and also new biomarkers for infection detection, treatment prognosis and relapse are needed. Extracellular Vesicles (EVs), are considered a resource with great potential for generating a higher understanding of complex biological processes and also as a potential source of biomarkers. To evaluate the potential of plasma EVs in the context of VL and to find new possible molecules of interest for disease management in the context of HIV/VL coinfection, EVs were recovered from the plasma of an HIV+VL+ patient over a two-year period, and compared to age and sex-matched HIV and HIV-VL- controls. The approach selected for plasma EVs recovery was Size-Exclusion Chromatography followed by fraction selection using common EVs markers and proteomic analysis of fractions of interest by MS. The proteomic analysis performed confirmed the identification of common EVs biomarkers. The capacity to detect Leishmania proteins was limited with no identifications with more than one UP existed. Moreover no Leishmania protein identification was common between time points. Concernng human proteins, several proteins were detected with distinct abundance in the patient compared to both control groups. Using GO approach, the proteins were associated with specific biological processes, like MHC-I that provide a complementary overview of the patient immunological condition. Among the proteins detected, we highlighted the Macrophage receptor with collagenous structure (MARCO). This protein was detected in the patient in 4 out of 5 time points. Significantly, MARCO was also detected in plasma EVs from 5 other VL patients that were analysed. The presence of MARCO in the plasma EVs preparations was also confirmed by Western Blot. In conclusion, it was demonstrated that EVs analysis in the context of VL can contribute to understand the ongoing pathological process. Moreover, these EV are a source of possible biomarkers for VL monitoring. MARCO was a protein of interest being only identified in the VL patients. Ultimately, further studies need to be performed to generate a critical mass of data on EVs in the context of this and other infections to generate improvements in the clinical management of these vulnerable populations.