This study examined the interplay of depression and different types of e-health interventions on breast cancer patients' perceived healthcare competence, emotional processing, and social well-being over time. The three e-health interventions--Internet Only as a control condition, CHESS (Comprehensive Health Enhancement Support System) Only, and CHESS with a Human Mentor, a cancer information specialist--provided varying degrees of interactivity and presence. A total of 328 women with breast cancer participated in one of the three interventions for a 6-month period. Women were further split into two groups based on reported levels of depression. For perceived healthcare competence and social well-being, results revealed significant interaction effects for intervention type by depression over time, such that breast cancer patients with higher levels of depression benefited most from the CHESS with Mentor intervention over the 6-month study period. For emotional processing, depressed cancer patients benefited more from the CHESS with Mentor than the other two interventions, regardless of time. These findings have (a) theoretical implications on how mental health factors can intersect with interactivity and presence to influence psychosocial outcomes, (b) conceptual implications for the role of human interaction within e-health systems, and (c) practical implications for the development of e-health interventions for cancer patients with depression.