This investigation utilized data from a previous laboratory-based study to examine the interactive contributions of trait involuntary stress responses (ISRs, e.g., rumination) and perceived familial social support (SS) on the hypothalamic-pituitary-adrenal axis (HPA; as indexed via salivary cortisol) response to acute stress in a sample of 128 adolescent girls ages 12 to 16. Participants completed a modified Trier Social Stress Test (TSST), and physiologic stress response was indexed via six salivary cortisol samples. Dimensions of ISRs and familial social support were entered into regression models to predict total cortisol circulation defined by area under the curve with respect to ground (AUCG; Pruessner et al., 2003) following the TSST. Neither ISRs or SS were associated with cortisol AUCG, nor was there an interactive effect of SS on relationships between ISRs and AUCG. Implications of present results and methodological recommendations for future investigations are discussed. This may be the first investigation to consider the interactive effects of ISRs and social support on adolescent girls' HPA responses. Greater understanding of these factors in this understudied demographic will improve translational science as well as inform risk assessment and intervention development.