A disturbance in the activity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported among individuals with HIV-1 infection. However, these studies have been carried out in the West where the infecting clade is clade B. HIV-1 infection is rapidly spreading in various parts of South East Asia, including India, where the HIV-1 infecting clade is largely clade C. An investigation of HPA axis activity in this type of infection is warranted since there are many structural differences between clades B and C. This study was carried out to investigate whether HIV-1 infection clade C interferes with the functions of the hippocampus and thereby affects the HPA axis. We tested the hypothesis that when hippocampus activity is disturbed, it leads to the development of neuropathogenesis in HIV-1 C-clade infected individuals. This study included asymptomatic HIV-1 seropositive individuals (n=117) and, age-matched, HIV-1 seronegative controls (n=29). Neuroendocrine function of the HPA axis was evaluated using plasma levels of cortisol, ACTH, and DHEA-S, both in the morning (0800-1000 hr) and evening (2000-2200 hr). A significant elevation of cortisol levels during A.M. and P.M. hours was observed in HIV-1 infected individuals when compared to the controls. Interestingly, no significant change in ACTH level was observed in HIV-1 seropositive subjects, either during A.M or P.M. Elevated levels of cortisol in HIV-1 seropositive subjects appear to be independent of ACTH and may be the result of a defective negative feedback mechanism. On the other hand, a significant decrease in the plasma levels of DHEA-S was observed during A.M. and P.M. hours in HIV-1 infected individuals, leading to an increased cortisol to DHEA-S ratio. Since increased levels of cortisol and decreased levels of DHEA-S are related to the development of neuropathogenesis, it is hypothesized that a study of the development of neurocognitive deficits among HIV-1 seropositive individuals in India is warranted.