Before the development of multidrug regimens for treatment of patients with HIV infection single or dual nucleoside therapy was the standard of care. The present study was designed to examine the relative short (12-week) and long-term (48-week) activity of zidovudine (ZDV) vs stavudine (d4T) vs the combination in antiretroviral naive patients. The study was modified so that lamivudine (3TC) was added to ZDV after 12 weeks of monotherapy. A total of 129 subjects entered the study; however, not all were followed for 48 weeks as the study was terminated early due to changing standards of care. The median baseline viral load and CD4 cell count were 10,008 copies/ml and 407 cells/mm(3), respectively. There were no significant differences in the initial (12-week) change in viral load across the three arms. The viral load reduction at 48 weeks was greater in the ZDV/ZDV plus 3TC arm, with an average change of -0.91 log(10) copies/ml than in the d4T alone (-0.47 log(10) copies/ml) or d4T plus ZDV (-0.33 log(10) copies/ml), p = 0.03 and 0.02, respectively. There was a marginally significant increase in the CD4 cell count at Week 12 in the d4T arm as compared to the ZDV/ZDV plus 3TC arm. In general the treatments were well tolerated. The combination of d4T plus ZDV did not result in additional antiviral suppression as compared to either drug alone at 12 weeks and appeared to have less antiviral activity after Week 12. Based on this study and other data, combining d4T and ZDV is not recommended.