The current focus on simplifying treatment regimens for patients with human immunodeficiency virus (HIV) infection has contributed to the interest in once-daily therapy. The triphosphate of didanosine (2',3'-dideoxyinosine or DDI) has a long intracellular half-life, which supports the use of didanosine in a once-daily dosing schedule. Early clinical studies found that changes in surrogate markers were similar whether didanosine was dosed once or twice daily, while toxic effects occurred less frequently with once-daily dosing. Didanosine once-a-day used in combination with other drugs has also been studied, and results of some of these trials are summarized in this paper.