Since studying the pathogenesis of dengue virus associated disease in humans has several limitations, an appropriate animal model is needed. Therefore, we investigated kinetics of viremia as well as humoral and cellular immune responses, after primary, secondary and tertiary heterologous dengue virus infections in cynomolgus macaques: these parameters were largely similar to those observed in natural human infection upon primary infection. Both antibody and T-cell responses measured were largely cross-reactive. Upon secondary infection with a heterologous virus serotype, T-cell responses specific for the primary infecting serotype were more pronounced, especially when the immune system was primed with dengue 1 virus. Measurement of transcription levels of pro- and anti-inflammatory cytokines in white blood cells upon primary and secondary infection generally showed a balanced response. In addition, a region of the NS2A protein of dengue viruses was identified that induces T-cell responses in macaques.