Malaria is the leading cause of morbidity and mortality in children in Uganda. The mechanisms whereby malaria parasites are eliminated, or how they may avoid the immune response remain poorly understood. We examined malaria-specific T-cell responses in a well-characterized cohort of African children in an endemic area where malaria transmission occurs throughout the year. In studies of asymptomatic children, we found a low frequency of malaria-specific T-cell responses (15/117), and these appeared to be clustered in older children (> or =4 years old). Both CD4- and CD8-mediated T-cell responses were detected against circumsporozoite surface protein (CSP) and merozoite surface protein-1 (MSP-1). The presence of these T cells did not correlate with the frequency of prior episodes of parasitemia and 5 out of the 15 responders had no documented parasitemia within 8-12 months prior to immunologic evaluation. Our data supports focusing on high-risk children in future preventive vaccination efforts to ensure the generation and maintenance of effective anti-malarial cellular immune responses.