Theoretically, subjective levels of anxiety and hostile attributions of intent may affect physiological responding to ambiguous social situations. This study examined youths’ (n = 80 aged 11–17 years; 51% female; 37.5% African American) physiological responding (i.e., heart rate [HR]) to a series of animated vignettes depicting ambiguous social situations. Anxiety, aggression, hostile attributional bias (HAB), and their interactions were tested as predictors of differential physiological responding to the vignettes. Results indicated that there was differential physiological responding to the vignettes such that, as predicted, participants’ hearts rates showed a pattern of deceleration followed by acceleration, similar to a threat response. There was support for elevated anxiety as a significant predictor of responses, but only among those participants with higher levels of HABs such that HRs remained elevated with very little deceleration across time. These results suggest a pattern of physiological hyperarousal and blunted reactivity for those with high anxiety and HABs indicating that that youths’ interpretation of a situation may interact with subjective levels of anxiety to predict heart rate responses.