Treatment guidelines for HIV-infected children recommend using combinations of reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs). Successful suppression of HIV replication and adherence to these regimens are often suboptimal because of multiple factors. For patients with detectable viremia and limited treatment options, therapy simplification consisting of RTIs, referred to as partial treatment interruption (PTI), may represent a temporizing option. We describe a cohort of 26 HIV-infected children who underwent treatment simplification by discontinuing the PI and continuing therapy with 2 or more RTIs. The subjects, who were identified retrospectively, were followed for a period of 24 to 96 weeks. Data collected included clinical information, viral load, and CD4T lymphocyte percentage (CD4%) at baseline and 24, 48, and 96 weeks after PTI. Twenty-six, 21, and 11 patients were evaluated at 24, 48, and 96 weeks, respectively. No child had Centers for Disease Control and Prevention-defined disease progression, and there were no significant changes in viral loads (P > 0.5) across all study intervals after interruption of the PIs. Although most children maintained a CD4% > 15%, comparisons of CD4% at 24 and 48 weeks demonstrated a statistically significant decrease compared with baseline. Therapy simplification by PTI may provide a practical option in patients intolerant of or failing PI-based highly active antiretroviral therapy.