Divorce is a stressor associated with long-term health risk, though the mechanisms of this effect are poorly understood. Cardiovascular reactivity is one biological pathway implicated as a predictor of poor long-term health after divorce. A sample of recently separated and divorced adults (N = 138) was assessed over an average of 7.5 months to explore whether individual differences in heart rate variability—assessed by respiratory sinus arrhythmia—operate in combination with subjective reports of separation-related distress to predict prospective changes in cardiovascular reactivity, as indexed by blood pressure reactivity. Participants with low resting respiratory sinus arrhythmia at baseline showed no association between divorce-related distress and later blood pressure reactivity, whereas participants with high respiratory sinus arrhythmia showed a positive association. In addition, within-person variation in respiratory sinus arrhythmia and between-persons variation in separation-related distress interacted to predict blood pressure reactivity at each laboratory visit. Individual differences in heart rate variability and subjective distress operate together to predict cardiovascular reactivity and may explain some of the long-term health risk associated with divorce.