It has been demonstrated that the cytomegalovirus (CMV)-specific CD4(+) T cell response could be restored after ganciclovir and highly active antiretroviral therapy (HAART) in AIDS patients. In this study, we first confirmed the above observation cross-sectionally. We then performed a prospective longitudinal study over a period of 48 weeks. The second study included nine patients. All patients had received HAART. Five patients had a history of retinitis that was, however, under control after discontinuation of anti-CMV therapy more than 1 year before this study (group A). The other four had active CMV retinitis at the start of this study and anti-CMV therapy was required to control retinitis (group B). Median periods between commencement of HAART and the start of this study in group A and in group B were 27 and 4.5 months, respectively. Within both groups, the number of CD4(+) T cells that produced tumor necrosis factor alpha in response to CMV antigen did not vary throughout the observation period (Friedman test; p > 0.05). However, the median number of responsive CD4(+) T cells in group A patients was significantly higher than in group B (p < 0.05). Our results demonstrate that the number of CMV-responsive CD4(+) T cells increased when HIV was well controlled with HAART and was then maintained, and suggest that these cells may play an important role in the control of retinitis in patients with AIDS.