Despite the longstanding appreciation of communication between the nervous and the immune systems, the nature and significance of these interactions to immunity remain enigmatic. Here, we show that 6-hydroxydopamine-mediated ablation of the mouse peripheral sympathetic nervous system increases primary CD8(+) T cell responses to viral and cellular antigens presented by direct priming or cross-priming. The sympathetic nervous system also suppresses antiviral CD4(+) T cell responses, but this is not required for suppressing CD8(+) T cell responses. Adoptive transfer experiments indicate that enhanced CD8(+) responses do not result from permanent alterations in CD8(+) T cell function in sympathectomized mice. Rather, additional findings suggest that the sympathetic nervous system tempers the capacity of antigen-presenting cells to activate naïve CD8(+) T cells. We also show that antiviral CD8(+) T cell responses are enhanced by administration of a beta(2) (but not beta(1) or alpha) adrenergic antagonist. These findings demonstrate a critical role for the sympathetic nervous system in limiting CD8(+) T cell responses and indicate that CD8(+) T cell responses may be altered in patients using beta-blockers, one of the most widely prescribed classes of drugs.