In summary, the present study demonstrates the application of diagnostic proteomics to decipher host responses against the human malaria parasites Pf and Pv, and identifies potential candidate biomarkers for these two plasmodial infections. In this comprehensive proteomic analysis we have identified multiple differentially expressed serum proteins with versatile biological functions, indicating the modulation of multiple vital physiological pathways in FM and VM patients. We anticipate that information obtained from this study will provide valuable insight into the underlying molecular mechanisms of malaria and may help to establish early detection surrogates for these infectious parasitic diseases to meet the need for better diagnostics and effective therapy. Some of our identified classifier proteins such as serum amyloid A, apolipoprotein A-I and E and haptoglobin, which successfully discriminated FM from VM might be prognostic host markers for disease severity. To this end, it would be interesting to elucidate the fate of the identified serum proteins in severe malaria patients and could be a future continuation of this study. Diagnostic impact of the identified serum biomarkers in clinics and specificity for malaria prediction can only be established after investigation of the disease patterns in large clinical cohorts.