The response of HIV-1 to initial zidovudine (ZDV) treatment was assessed in 11 patients with severe HIV disease. We quantified serum HIV-1 concentrations and mutations associated with ZDV resistance by culture-independent methods. There was a prompt fall in serum HIV-1 RNA within 1-2 days of treatment with maximum suppression by seven days, which was paralleled by changes in serum p24 antigen (p24 Ag). Serum RNA started to return to pretreatment levels within weeks. The HIV reverse transcriptase (RT) gene in most patients developed mutations associated with drug resistance within months and as early as 25 days on therapy in one patient. The codon changes were not sufficient to explain the early return of serum HIV-1 RNA levels and their patterns continued to evolve after patients stopped taking ZDV. The significance of these findings is discussed in relation to the limited long-term efficacy of ZDV. The dynamic time course of viral load and RT responses to ZDV is of particular importance in short-term interventions such as pregnancy.