We describe an unintentional significant overdose of darunavir in a treatment-experienced adolescent with decreased darunavir susceptibility and prior treatment failure on darunavir therapy. Minimal toxicity and improved virologic suppression observed with an overdose have prompted consideration of the continued use of a higher than recommended dose. Pharmacokinetic and pharmacodynamic evaluations justified the individualized use of high-dose darunavir, which resulted in virologic suppression, improved CD4 cell count, and resolution of toxicity.