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Objective: Randomized controlled trials (RCTs) of early palliative care interventions in advanced cancer have positively impacted patient survival, yet the mechanisms remain unknown. This secondary analysis of 2 RCTs assessed whether an early palliative care intervention moderates the relationship between depressive symptoms and survival. Method: The relationships among mood, survival, and early palliative care intervention were studied among 529 advanced cancer patients who participated in 2 RCTs. The first (N = 322) compared intervention versus usual care. The second (N = 207) compared early versus delayed intervention (12 weeks after enrollment). The interventions included an in-person consultation, weekly nurse coach-facilitated phone sessions, and monthly follow-up. Mood was measured using the Center for Epidemiologic Studies-Depression (CES-D) scale. Cox proportional hazard analyses were used to examine the effects of baseline CES-D scores, the intervention, and their interaction on mortality risk while controlling for demographic variables, cancer site, and illness severity. Results: The combined sample was 56% male (M = 64.7 years). Higher baseline CES-D scores were significantly associated with greater mortality risk (hazard ratio [HR] = 1.042, 95% confidence interval [CI] [1.017, 1.067], p = .001). However, participants with higher CES-D scores who received the intervention had a lower mortality risk (HR = .963, CI [0.933, 0.993], p = .018) even when controlling for demographics, cancer site, and illness-related variables. Conclusion: This study is the first to demonstrate that patients with advanced cancer who also have depressive symptoms benefit the most from early palliative care. Future research should be devoted to exploring the mechanisms responsible for these relationships.