Clinical histories are reported for 2 patients treated with highly active antiretroviral therapy (HAART) who experienced multiple relapses of cytomegalovirus (CMV) retinitis, despite suppression of human immunodeficiency virus type 1 (HIV-1) viremia and improvement in CD4⁺ T cell counts (to >400 cells/μL). CMV-specific CD4⁺ T cell immune reconstitution was measured directly, using cytokine flow cytometry, which revealed persistent deficits in CMV-specific CD4⁺ T cell responses in both patients. CMV-specific T cells constituted 0.14% and 0.05% of the total CD4⁺ T cell count in these patients, which is significantly lower than the percentages for 34 control subjects (0.6%–46%; CD4⁺ T cell count range, 7–1039 cells/μL; P=.019). Deficits in pathogen-specific immune responses may persist in some individuals, despite suppression of HIV-1 replication and substantial increases in circulating CD4⁺ T cells after HAART, and such deficits may be associated with significant morbidity from opportunistic infections