The present study examines the association between disease-related factors, perceived social support, attachment security (i.e. attachment anxiety and avoidance), and the occurrence of depressive symptoms in a sample of patients with metastatic gastrointestinal or lung cancer. Results from a sample of 326 cancer outpatients with advanced disease indicate that disease-related factors are significantly associated with the occurrence of depressive symptoms, and the latter are inversely related to the degree of attachment anxiety and avoidance, and perceived social support. Attachment security (on the dimension of anxious attachment) significantly buffered the effect of disease-related factors on depressive symptoms, and perceived social support mediated the relationship between attachment security and depressive symptoms. The buffering effect of attachment security on depressive symptoms and its partial mediation through social support suggest that the interaction of individual, social, and disease-related factors contribute to the emergence of depressive symptoms in patients with metastatic cancer.