Dideoxyinosine (ddI) and interferon-alpha have both been shown to have anti-HIV activity in vitro as well as in patients. However, single agent therapy appears inadequate over the long term to control HIV infection. Combination therapy with 2 or more effective antiretroviral agents may decrease disease progression, prevent the development of resistant HIV isolates, and decrease the toxicity of therapy. To evaluate the interaction of these two agents, 36 patients (3 patients per group) were enrolled in a dose escalation study. Three doses of ddI and four doses of interferon-alpha were evaluated. In addition, 14 patients with prior AZT and interferon therapy were also included to evaluate the effect of changing the nucleoside analog from AZT to ddI. Patients were monitored for toxicity as well as efficacy, as evaluated by changes in counts and p24 antigen. Pharmacokinetics were performed to determine the interaction of ddI and interferon. All patients have completed the active therapy phase of this study. Declines in p24 antigen have been seen with combination therapy as well as with ddI alone. Trends toward an elevation in CD4 number and percent have been seen, but because this is an open study, it is difficult to be sure that this is related to therapy. Four patients developed clinical pancreatitis, and two developed asymptomatic amylase elevations. Four patients developed a peripheral neuropathy. Seventeen patients have continued on combination therapy for a period of up to four years, during which time they have shown continued apparent benefit from combination therapy, as evidenced by stable CD4 counts and p24 antigen levels. These patients will continue to be followed to determine the long-term safety and potential efficacy of this combination. The goal of this study is to develop effective anti-retroviral therapy that is well-tolerated, and associated with long-term benefit.