The factors that predict academic performance are of substantial importance yet are not understood fully. This study examined the relationship between cardiovascular markers of challenge/threat motivation and university course performance. Before the first course exam, participants gave speeches on academics-relevant topics while their cardiovascular responses were recorded. Participants who exhibited cardiovascular markers of relative challenge (lower total peripheral resistance and higher cardiac output) while discussing academic interests performed better in the subsequent course than those who exhibited cardiovascular markers of relative threat. This relationship remained significant after controlling for two other important predictors of performance (college entrance exam score and academic self-efficacy). These results have implications for the challenge/threat model and for understanding academic goal pursuit.