Co-infections such as Mycobacterium tuberculosis (TB) and Pneumocystis pneumonia may affect the progress of HIV infection and speed the onset of death. As malaria and syphilis are both endemic in West Africa we examined their effects on HIV-2 infection, for these may also accelerate the progress of disease. A community-based case-control study was undertaken in a rural village in Guinea-Bissau, West Africa. One hundred and fifty asymptomatic subjects seropositive for HIV-2 and 154 age- and sex-matched controls were enrolled. Venous blood samples taken into EDTA were stained within six hours of collection with CD4 and CD8 monoclonal antibodies and processed by Q-Prep machine in the field. The stained cells were then transported on ice by road and analysed by FACS-can at the base laboratory in The Gambia within a week. The mean CD4% was significantly lower and geometric mean neopterin and beta 2-microglobulin levels were significantly higher in the HIV-2-infected subjects than in the controls (P < 0.01 for all cases versus all controls). The mean CD4% was lower and beta 2-microglobulin level was higher in both HIV-2 and control subjects with active or past syphilis when compared with subjects with no syphilis; however, syphilis did not have a marked effect on plasma neopterin level. Malaria infection raised neopterin levels, but had little effect on CD4%. Overall multiple regression analysis allowing for HIV-2 infection and other variables showed that syphilis lowered CD4% (P = 0.01) and raised beta 2-microglobulin levels (P = 0.05) and malaria raised neopterin levels (P = 0.05). The conclusions are that HIV-2 infection is associated with lower CD4% and higher neopterin and beta 2-microglobulin levels than controls, and co-infection with syphilis is associated with a further lowering of CD4%, suggesting a worse suppression of the immune system. Co-infection with malaria is associated with a modest immune disturbance.