Context A growing epidemiological literature has suggested that marital discord is a risk factor for morbidity and mortality. In addition, depression and stress are associated with enhanced production of proinflammatory cytokines that influence a spectrum of conditions associated with aging. Objective To assess how hostile marital behaviors modulate wound healing, as well as local and systemic proinflammatory cytokine production. Design and Setting Couples were admitted twice to a hospital research unit for 24 hours in a crossover trial. Wound healing was assessed daily following research unit discharge. Participants Volunteer sample of 42 healthy married couples, aged 22 to 77 years (mean [SD], 37.04 [13.05]), married a mean (SD) of 12.55 (11.01) years. Interventions During the first research unit admission, couples had a structured social support interaction, and during the second admission, they discussed a marital disagreement. Main Outcome Measures Couples’ interpersonal behavior, wound healing, and local and systemic changes in proinflammatory cytokine production were assessed during each research unit admission. Results Couples’ blister wounds healed more slowly and local cytokine production (IL-6, tumor necrosis factor α, and IL-1β) was lower at wound sites following marital conflicts than after social support interactions. Couples who demonstrated consistently higher levels of hostile behaviors across both their interactions healed at 60% of the rate of low-hostile couples. High-hostile couples also produced relatively larger increases in plasma IL-6 and tumor necrosis factor α values the morning after a conflict than after a social support interaction compared with low-hostile couples. Conclusions These data provide further mechanistic evidence of the sensitivity of wound healing to everyday stressors. Moreover, more frequent and amplified increases in proinflammatory cytokine levels could accelerate a range of age-related diseases. Thus, these data also provide a window on the pathways through which hostile or abrasive relationships affect physiological functioning and health.