Background: According to the NIH consensus statement, the three most common and debilitating symptoms for cancer patients are depression, pain and fatigue. The aims of this study were to test the efficacy of a web-based collaborative care intervention to reduce cancer-related symptoms and improve quality of life in advanced cancer patients. Methods: Patients with advanced cancer were randomized to a web-based stepped collaborative care intervention or usual care arm. The primary outcomes of the intervention included the Center for Epidemiological Studies-Depression (CES-D), Brief Pain Inventory, the Functional Assessment of Cancer Therapy (FACT)-Fatigue, and the FACT-Hepatobiliary. Secondary outcomes included Interleukin (IL)-1b, IL-6 and Natural Killer cells and the Caregiver Quality of Life Index and Caregiver CES-D. An intent to treat analyses was performed and effect sizes were reported using the Cohen’s d (Small<0.20; Medium=0.30-0.70; Large>0.80) or Phi (Small=0.10; Medium=0.30; Large=0.50). Results: A total of 261 patients and 179 caregivers were enrolled in the study. Patients with clinical levels of symptoms, who were randomized to the intervention arm, reported reductions in depression (Cohen’s d=0.32), pain (Cohen’s d=0.74), fatigue (Cohen’s d=0.48) and improvements in quality of life (Cohen’s d =0.38) when compared to patients randomized to the usual care arm at 6-months. Patients randomized to the intervention arm also had reductions in IL-6 (Phi=0.34), IL-1b (Phi=0.38) and increases in NK cell numbers (Phi=0.49). The family caregivers of patients randomized to the intervention arm also had lower levels of stress (Cohen’s d=0.75) and depressive symptoms (Cohen’s d=0.37) when compared to the usual care arm at 6-months. Conclusions: The web-based collaborative care intervention was found to be effective in reducing cancer-related symptoms, immune system dysregulation, and improving quality of life in both the patients and family caregivers. Clinical trial information: NCT01640522.