Caregivers for spouses with Alzheimer's disease and related dementias (ADRD) experience drastic changes in the marital relationship that may put them at risk for worsening well-being. Perceived partner responsiveness, or feeling cared for, understood, and appreciated by one's spouse, may help mitigate these effects. In this study, we investigated the associations between marital distress, perceived partner responsiveness, and psychological and physiological well-being indicators among ADRD spousal caregivers. Method A sample of 161 caregivers provided blood samples and completed self-report measures of marital distress, perceived partner responsiveness, and depressive symptoms. We tested hypotheses in our sample cross-sectionally based on two theoretical frameworks. Results Testing the marital discord model of depression, caregivers who reported greater marital distress also reported more depressive symptoms, and this association was stronger as participants reported lower perceived partner responsiveness. Caregivers who reported greater marital distress exhibited elevated proinflammatory cytokine production by in vitro lipopolysaccharide (LPS)-stimulated peripheral blood leukocytes at low levels of perceived partner responsiveness, but not mean or high levels. Testing the vulnerability-stress-adaptation model, caregivers who reported more depressive symptoms also reported greater marital distress. Further, caregivers who exhibited elevated LPS-stimulated proinflammatory cytokine production reported greater marital distress at mean and high levels of perceived partner responsiveness, but not low levels. These patterns of results held even when accounting for the dementia stage and reported hours of caregiving per day. Discussion This study's findings contribute to the body of research examining interpersonal factors that shape health and well-being among the caregiver population.