The present study was undertaken to investigate the possible role of a 10-kDa, secretory antigenic protein of Mtb (MTSA-10) in regulating macrophase response to lipopolysacchride (LPS). MTSA-10 inhibited the lipopolysaccharide (LPS)-induced oxidant species generation in the macrophage. Treatment of macrophages with MTSA-10 activated their protein tyrosine phosphatases (PTPs) in a redox-regulated fashion. These activated phosphatases then interfered with the early events of LPS signaling and lower the strength and magnitude of the signal generated, thereby preventing macrophages from making an effective immune response. Mycobacterium tuberculosis Region of Deletion-1 (RD-1)-specific secretory antigen MTSA-10 (encoded by ORF Rv3874 of Mtb genome) modulated the macrophage signaling machinery and prevented it from responding to further activation by LPS.