The rapid rise of Monkeypox (MPX) cases outside previously endemic areas prompt for a better understanding of the disease. We studied the plasma proteome of a group of MPX patients with a similar infection history and clinical manifestation typical for the current outbreak. We report that MPX is associated with a strong plasma proteomic response among nutritional and acute phase response proteins. Moreover, we report a correlation between plasma proteins and disease severity. Contrasting the MPX host response with that of COVID-19, we find a range of similarities, but also important differences. For instance, CFHR1 is induced in COVID-19, but suppressed in MPX, reflecting the different role of the complement system in the two infectious diseases. The partial overlap in response proteins, however, allowed us to explore repurposing of a COVID-19 biomarker panel assay, which resulted in successful patient classification. Hence, our results provide a first proteomic characterization of the MPX human host response, and we reveal a thus far untapped potential for accelerating the response to disease outbreaks through the repurposing of biomarker assays.