Among the four different species of Plasmodia, which cause malaria in human, Pf and Pv account for over 90% of the total malaria cases worldwide. In this study, we used proteomics to decipher the alteration in human serum proteome due to the Pf infection to gain insight into the disease pathogenesis and host immune response. We also performed a comparative analysis of host response in Pf and Pv infection. The comparative proteomic analysis of plasmodial and leptospiral infection (febrile control) was performed to appraise the generic febrile responses and specify the malaria related serum markers. The ultimate aspiration of this study was to identify potential marker proteins that can distinguish the malaria patients from the healthy or febrile controls as well as discriminate between the Pf and Pv infections with high accuracy. Although a number of earlier proteomic and immunoassay-based studies have demonstrated the alteration of limited set of serum proteins in malaria [16] [17] [18] hitherto, there was no attempt for a comprehensive analysis to establish a panel of classifier proteins that can readily discriminate the FM and VM groups from the controls.