This study reports on the role of cocaine as effect modifier of the association of CD4+ cell counts and RNA viral load. HIV-1 seropositive (n = 80) and seronegative (n = 42) African American women (AAW) crack cocaine smokers were recruited. Increasing cocaine use, based on self-reports and laboratory values, significantly exacerbates the immunopathology of HIV-1 in a dose-response manner, confirmed by a non-linear drop in CD4+ cell number for a given viral load in HIV+ AAW. This report supports a view of deleterious effects due to cocaine use in humans.