We aimed to determine, in an observational retrospective study, whether baseline HTV-1 RNA is an independent predictive factor for the emergence of a genotype associated with zidovudine resistance and whether previously identified predictive factors remain independent when viraemia is taken into account. Fifty nucleoside-naive HIV-1-infected individuals initiating zidovudine therapy (in 11 cases associated with didanosine) were submitted to clinical, immunological and virological monitoring at entry and every 12 weeks thereafter. The critical endpoint of the study was the influence of key baseline characteristics (CD4 cell counts, clinical stage, HIV-1 p24 antigen, virus phenotype and viraemia) upon the time to development of mutation at codon 215. The presence of serum p24 antigen, syncytium-inducing (S1) phenotype, a HIV-1 RNA load greater than the median (32495 RNA copies/ml), CD4 cell counts lower than 200/mm3 and clinical CDC category C were all baseline features associated with more rapid development of the mutant RT215 genotype in the univariate analysis. However, a multivariate Cox proportional hazard stepwise regression analysis showed that only baseline p24 antigenaemia, SI phenotype and a HIV-1 RNA load greater than 32495 RNA copies/ml were sequentially selected as independent predictive factors for the development of the mutant genotype. The present study suggests that baseline HIV-1 RNA load is an independent predictive factor for the development of a zidovudine resistance genotype. Likewise, it reinforces the independent predictive value of serum p24 antigenaemia and SI phenotype, even when viraemia is taken into account.