Background The relational impact of advanced cancer on both patients and spouse caregivers has rarely been examined simultaneously. This study describes a framework for understanding distress in each partner as a consequence of psychosocial characteristics, burden of disease or of caregiving, and the distress of the other person. A model focusing on the protective value of social relatedness was tested to illustrate the interdependence of patients and spouses in their mutual adaptation to disease. Methods A total of 278 advanced cancer patients and their spouse caregivers completed measures of psychological distress (e.g., depression), physical burden from cancer (e.g., symptom count), caregiving burden (i.e., time and task demand), and social relatedness (i.e., social support and attachment security). Structural equation modeling was used to extract latent factors associated with these constructs and to examine their interrelationships. Results The model fit was adequate. Patient distress was related to disease burden (standardized path coefficient = 0.52) and patient social relatedness (−0.32). Caregiver distress was related to caregiving burden (0.21) and caregiver social relatedness (−0.51). Caregiving burden was related to patient disease burden (0.43) and caregiver social relatedness (−0.37). Reciprocal pathways between patient and caregiver distress indicated that caregiver distress was influenced by patient distress (0.30) but not vice versa (0.12). Conclusions These findings support the view that patients and caregivers constitute an interdependent relational system and interventions in this setting should take into account both interactions between patients and caregivers and the nature of their social relatedness. Copyright © 2013 John Wiley & Sons, Ltd.