Drug resistance patterns and their correlation to treatment response 24 weeks after addition of lamivudine to a previous zidovudine/zalcitabine or zidovudine/ didanosine combination treatment, or after substitution of lamivudine for the zalcitabine or didanosine in these combinations, were evaluated in 21 patients with CD4 counts between 50 and 300 cells/mm(3). immunological and virological outcomes were measured at baseline and at weeks 4, 12 and 24. Drug resistance was assessed using the recombinant virus assay and direct solid-phase sequencing of the reverse transcriptase gene. Viral load decreased by an average of 0.78 log RNA copies/ml at week 4, but returned to baseline at week 24 for most patients. CD4 cell counts increased in all treatment groups without reaching statistical significance. Resistance to lamivudine was readily acquired in all four treatment groups and was often associated with a partial reversal of phenotypic zidovudine resistance and a moderate increase in the 50% inhibitory concentrations for didanosine and zalcitabine. One patient receiving the zidovudine/didanosine combination treatment harboured multi-nucleoside analogue-resistant virus. A poor response to lamivudine tended to be related to the extent of pre-existing zidovudine resistance.