We investigated the extent to which individual differences in activity of the hypothalamic pituitary adrenal axis (HPA) are associated with depressive symptoms among newlywed couples. Participants were 218 couples (M age 28.4 years; 94% White) who provided 5 saliva samples (later assayed for cortisol and DHEA-S) before and after participation in a discussion of a major area of disagreement in their relationship. Depressive symptoms were assessed initially, and approximately 19- and 37-months later. Results revealed an interactive effect suggesting that concordant levels of cortisol and DHEA-S (either both high or both low) were concurrently and prospectively associated with higher depression scores. Interestingly, this interactive effect was observed for wives only - not for husbands. These observations underscore contemporary theoretical assumptions that the expression of the association between HPA activity and depression is dependent on factors related to the interaction between characteristics of the person and features of the social environment, and moderated by co-occurring variation in endocrine milieu.