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Young women typically use same-sex friendships as a source of social support during times of stress. However, friendship interactions that are characterized by co-rumination, excessive problem discussion and negative affect focus, while related to quality friendships, are also related to internalizing symptoms. The goal of the current study was to better understand how the hypothalamic—pituitary—adrenal axis (salivary cortisol) and sympathetic nervous system (salivary alpha-amylase, sAA), react to co-rumination. Observed co-rumination predicted increased cortisol responses while negative affect focus during problem discussion predicted increases in both cortisol and sAA. These findings suggest that dual system activation may be at least one physiological pattern that links co-rumination to increased internalizing symptoms, even in the context of a high-quality friendship.