Nineteen children with human immunodeficiency virus (HIV) infection were treated with recombinant human gamma interferon (rIFN-) (50 µg/m² subcutaneously three times each week during weeks 1 through 12 and 100 µg/m² subcutaneously three times each week during weeks 13 through 24) in a phase I/II clinical trial. All children continued to receive previously prescribed therapy with oral zidovudine or didanosine. Children were assessed clinically and with laboratory studies during 24 weeks of study treatment and for 12 weeks after completion of rIFN- therapy. In general, rIFN- therapy was well tolerated. There were two clinical or laboratory adverse events thought to be possibly or probably study drug associated. One child developed acute pancreatitis; another child developed granulocytopenia. Median CD4⁺-lymphocyte counts and plasma HIV RNA concentrations did not change significantly during therapy. In vitro neutrophil bactericidal activity against Staphylococcus aureus and superoxide production were not significantly affected by rIFN- therapy. We conclude that rIFN- therapy in HIV-infected children receiving single-agent antiretroviral therapy is safe and does not produce consistent changes in CD4⁺-lymphocyte count, plasma HIV RNA concentration, or in vitro neutrophil function.