In this multicenter, randomized, double-blind study the activity of polyI:polyC₁₂U administered with zidovudine was evaluated in the treatment of HIV infection. Thirty-six HIV-positive, pre-AIDS individuals (100–500 CD4⁺ cells/mm³) who had had at least six months of zidovudine therapy received polyI:polyC₁₂U (400 or 700 mg) or placebo twice weekly with zidovudine. PolyI:polyC₁₂U subjects with baseline CD4⁺ counts≥300/mm³ showed a trend towards reduced CD4⁺ loss versus placebo recipients. PolyI:polyC₁₂U subjects were more likely to exhibit positive delayed-type hypersensitivity responses than placebo recipients. Placebo subjects crossing over to polyI:polyC₁₂U therapy demonstrated improved CD4⁺ and delayed-type hypersensitivity responses. PolyI: polyC₁₂U subjects with baseline CD4⁺ counts≥300/mm³ were less likely to develop AIDS than similar placebo subjects. PolyI:polyC₁₂U therapy of HIV-positive subjects restored or stabilized immune function as indexed by delayed-type hypersensitivity reactivity and, in individuals with CD4⁺ counts>300/mm³, abrogated CD4⁺ loss and reduced disease progression. PolyI:polyC₁₂U was generally well-tolerated in this zidovudine-treated population. No subject discontinued therapy due to an adverse reaction or aberrant laboratory parameter.