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The objective of this randomized, double-blind, controlled multicentre study was to evaluate the efficacy of saquinavir alone or in combination with zalcitabine compared to zalcitabine monotherapy in reducing progression of human immunodeficiency virus (HIV) disease. Nine hundred and forty HIV-infected patients with more than 16 weeks of prior zidovudine therapy and pre-study entry CD4 cell counts between 50 and 300 cells/mm3were randomized to saquinavir 600 mg every 8 h, zalcitabine 0.75 mg every 8 h or the combination of both drugs. In an intent-to-treat analysis, the treatment arms were balanced with respect to demographics, baseline HIV RNA (mean 5.0 log10copies/ml) and CD4 lymphocyte count (mean 170 cells/mm3). More patients in the zalcitabine arm stopped therapy because of toxicity than in the other two arms (25% versus 16%; P=0.005). Peripheral neuropathy was the most common treatment-limiting toxicity. Fifty-one patients in the saquinavir plus zalcitabine group developed an AIDS-defining event or died compared to 84 and 88 in the saquinavir and zalcitabine monotherapy groups respectively. Combination treatment with saquinavir plus zalcitabine reduced the risk of progression to AIDS by 49% (95% confidence interval 0.36 to 0.72, P=0.0001) and reduced death by 68% (95% confidence interval 0.16 to 0.64, P=0.001) compared to zalcitabine monotherapy. The addition of saquinavir to zalcitabine resulted in a significant reduction in progression to AIDS or death compared with zalcitabine alone.