To ascertain whether combination therapy with zidovudine (AZT) and zaleitabine (ddC) delayed the emergence of AZT resistance, isolates of human immunodeficiency virus (HIV) were evaluated from 15 previously untreated patients with advanced HIV disease who received combination therapy. Eighteen sequential viral isolates were available from 15 patients who received −6 months of combination therapy. Isolates from eight (73% of 11 patients obtained between 24 and 48 weeks of therapy were AZT resistant [50% inhibitory concentration (1C50)of 40–45 μM range. 0.45–2.0 μM]. Four of these eight patients yielded virus isolates that were highly AZT resistant (IC50(μM). NO changes in ddC susceptibility were discerned. The median IC50, for ddC was 0.2 μM and ranged from 0.07 to 0.5 μM. The CD4 cell counts of patients with AZT -sensitive virus tended to have higher median areas under the curve (AUC) and greater increases compared with patients who had AZT-resistant virus. They also had higher means and ranges of the average CD4 154 cell counts at week 36 (p 0.01) and week 48 (p - 0.04). These data would indicate that the previously described more sustained CD4 cell responses conferred by the addition of ddC to AZT therapy cannot be ascribed to delayed emergence of AZT resistance with combination therapy.