OBJECTIVE To evaluate if the combination of AZT/ddl offered any advantages in surrogate markers among HIV infected asymptomatic patients previously treated with AZT for at least six months. METHODS We used a prospective cohort of 269 asymptomatic HIV patients with CD4+ cell counts between 200 and 500 cells/microL. They were given didanosine (ddl 400 mg/d) in addition to AZT (500 mg/d) and had received AZT monotherapy for an average of 20 months. End points were progression to AIDS, death, or toxicity. RESULTS Median CD4+ cell count at the start of the combination therapy was 339 cells/microL which increased at three months to 451 and subsequently declined at 6, 12 and 18 months of followup (medians of 392, 360, 307 cells/microL respectively). Five patients progressed to AIDS, six developed toxicity (myelosuppression, hepatitis or pancreatitis) and 26 had minor side effects that required only dose reduction. CONCLUSIONS The addition of ddl to patients with prolonged ZDV monotherapy can be useful. CD4+ T cell counts showed a significant increase at 3 months with a gradual subsequent decline to below baseline at 18 months. Adverse effect of the drugs, although frequent, did not stop therapy in most patients.