Background: Mono-infections of Plasmodium spp., hepatitis B virus (HBV), and Mycobacterium tuberculosis could elicit activation of complements for innate immunity leading to inflammatory responses. Objective: This work was designed to determine host immune responses to mono-infections of Plasmodium spp., HBV, and M. tuberculosis in blood complement 3 (C3), complement 5 (C5), tumor necrosis factor-alpha (TNF-α), and interleukin 10 (IL-10). Materials and Methods: Of 200 volunteers 66 Plasmodium spp., mono-infected, 28 HBV mono-infected, 12 M. tuberculosis mono-infected and 62 noninfected volunteers were studied as test and controls. ELISA was used to determine HBV, hepatitis C virus (HCV), HIV, plasma C3, C5, IL-10, and TNF-α while Plasmodium spp., was identified by Geimsha thick-film microscopy and M. tuberculosis by immunofluorescence microscopy. Results: The results obtained in the 200 volunteers showed. 69% (138) were infected with one or more of Plasmodium, HBV, HCV, HIV, and M. tuberculosis; 31% (62) were not infected; 16% (32) had co-infections of at least two of Plasmodium, HBV, HCV, HIV, and M. tuberculosis; 33% (66) were Plasmodium spp., mono-infected 14% (28) were HBV mono-infected while 6% (12) were M. tuberculosis. mono-infected. There was a significant increase in the plasma C3 in M. tuberculosis mono-infection compared with Plasmodium mono-infection; HBV mono-infection and control (P < 0.05). There was a significant increase in the plasma C3 in Plasmodium mono-infection compared with HBV mono-infection and control (P < 0.05) There was a significant decrease in the plasma C3 in the results obtained in HBV mono-infection compared with the control (P < 0.05). There was a significant increase in the plasma C5 in M. tuberculosis mono-infection compared with Plasmodium mono-infection; HBV mono-infection and control (P < 0.05). There was a significant increase in the plasma C5 in Plasmodium mono-infection compared with HBV mono-infection (P < 0.05). There was a significant decrease in plasma IL-10 and increased plasma TNF-α in Plasmodium, M. tuberculosis, and HBV mono-infections compared with the control (P < 0.05). There was also a significant increase in plasma TNF-α in M. tuberculosis mono-infection compared with Plasmodium mono-infection (P < 0.05). Conclusion: There was an evidence of host immune responses as evidenced by a significant increase in plasma C3, C5, and TNF-α including a decrease in IL-10 in mono-infections of Plasmodium spp., HBV and M. tuberculosis.