Didanosine enteric-coated should be taken on an empty stomach, but the once-daily combination of indinavir/ritonavir can be taken with food. Because these drugs are frequently included in 1 regimen, the food effects on the pharmacokinetics were evaluated. This was a randomized, 4-way crossover study of single doses of didanosine enteric-coated 400 mg and indinavir/ritonavir 1200/400 mg in 8 healthy subjects. The following regimens were given: didanosine enteric-coated 2 hours after breakfast (reference regimen A), indinavir/ritonavir with breakfast (reference regimen B), didanosine enteric-coated + indinavir/ritonavir 2 hours after breakfast (test regimen C), and didanosine enteric-coated + indinavir/ritonavir with breakfast (test regimen D). Breakfast was 550 kcal, 28% fat. Blood samples were drawn before and up to 24 hours after ingestion. Statistical comparisons of test regimens C and D with reference regimens A and B were made using the equivalence approach for indinavir and didanosine area under the curve and C(max) (0.80-1.25). Eight subjects (5 men, 3 women) were enrolled and completed the study. Indinavir area under the curves were bioequivalent in test regimens C and D compared to reference regimen B. A 14% increased C(max) was observed in test regimen C. Didanosine area under the curve in test regimen D was 4% lower and suggestive of bioequivalence compared to reference regimen A. However, test regimen C didanosine area under the curve was 23% lower and bioinequivalent compared to reference regimen A. Didanosine C(max) decreased 42% and 46% in test regimens C and D, respectively, in comparison to reference regimen A. In this study, dosing didanosine enteric-coated 400 mg once daily + indinavir/ritonavir 1200/400 mg once daily with breakfast indicated no decrease in the amount of absorption for either didanosine and indinavir and that this regimen could be administered with food.