The functions of natural killer (NK) cells and their interleukin-2-deducible counterparts, lymphokine-activated killer (LAK) cells, are often impaired in human immunodeficiency virus (HIV)-infected individuals. A statistical approach was used to establish if changes in LAK activity were associated with antiviral drug therapy, HIV-1 burden, or lymphocyte subset alterations. Our study group included 61 HIV-positive subjects without any opportunistic infections (OI-), 16 of whom received zidovudine (AZT), and 97 HIV-positive individuals with AIDS-related infection (OI+), 50 of whom received AZT. As expected, there was a stepwise decrease in total lymphocyte numbers in OI+ groups as a result of the selective loss of CD4+ cells. The groups receiving AZT therapy had fewer CD4+ cells but lower circulating p24 antigen levels than corresponding untreated groups did. No significant changes in the relative proportions or absolute numbers of CD56+ subsets in HIV-positive groups could be ascribed to OI status or AZT intervention. LAK cell cytotoxic responses, measured as LU20 values (which give a measure of 20% cytolysis of target cells), lysis per unit CD56+ NK cell, or lysis per unit blood volume, declined in OI+ groups. No main or interactive effects of AZT therapy on LAK activities were observed. Multivariate general linear models were used to determine the interactive effects of NK- and T-cell subsets on measured LAK cell numbers were added negative and positive predictors of LAK activity, respectively. These findings indicate that declines in NK-mediated LAK cell responses serve as functional correlates of progression in HIV-infected individuals.