During a randomized double-blind study to assess the antiviral activity of saquinavir (SQV) alone or in combination with zidovudine (ZDV), the emergence of phenotypic resistance was evaluated in 44 patients treated with SQV (13 subjects), ZDV (14 subjects), and SQV plus ZDV (17 subjects). A significant (P< 0.05) lower CD4+ cell count and higher HIV RNA copy number at entry were found in six patients who developed resistant viral strain (3 to ZDV and 3 to SQV) during the first 4 months of treatment. After 1 year, drug-resistant strains (12 to ZDV and 14 to SQV) were isolated in 26 out of 37 patients. A significant higher number of patients treated with ZDV alone (10/13) harbored ZDV-resistant strains compared to patients treated by combination therapy (2/13); whereas more than 50% of patients had SQV-resistant strains aside from treatment. Early SQV-resistant strains were isolated in a limited number of patients treated with SQV alone (3/13). The rates of emergence of resistant strains during ZDV or SQV monotherapies are comparable. Combination therapy may delay the emergence of phenotypic resistance to either drugs in the short term and to ZDV, but not to SQV, at least after 1 year.