The relationship between plasma human immunodeficiency virus (HIV) RNA levels and peripheral CD4⁺ T cell counts was examined in 380 HIV-infected adults receiving long-term protease inhibitor therapy. Patients experiencing virologic failure (persistent HIV RNA >500 copies RNA/mL) generally had CD4⁺ T cell counts that remained greater than pretherapy baseline levels, at least through 96 weeks of follow-up. The CD4⁺ T cell response was directly and independently related to degree of viral suppression below the pretreatment baseline. For any given HIV RNA level measured 12 weeks after virologie failure, subsequent CD4⁺ T cell decline was slower in patients receiving a protease inhibitor-based regimen than in a historical control group of untreated patients. These observations suggest that transient or partial declines in plasma HIV RNA levels can have sustained effects on CD4⁺ T cell levels.