The feasibility of rectal administration of didanosine (DDI) was studied in six human immunodeficiency virus-infected patients. After oral intake of a DDI solution (100 mg/m² of body surface area) combined with an antacid (Maalox), pharmacokinetic parametric values were in accordance with previously published data; the mean ± standard deviation for terminal half-life was 59.5 ± 15.0 min, that for peak concentration was 5.2 ± 3.9 µmol/liter, and that for the area under the time-concentration curve (AUC) was 494 ± 412 min · µmol/liter. After rectal administration of a similarly prepared DDI solution (100 mg/m² of body surface area), plasma DDI levels were below the detection limit (0.1 µmol/liter) at all time points in five of the six patients, and in the remaining patient the AUC after rectal application was only 5% of that after oral administration. We conclude that oral administration of DDI cannot be easily replaced by rectal application.