Background: The aims of this study were to screen patients for symptoms of depression, pain, and/or fatigue and test the efficacy of a stepped collaborative care (SCC) intervention compared to standard of care (SC). When compared to SC, we expected that the patients randomized to the SCC intervention would report greater improvements in patient quality of life (QoL) and lower health care utilization and costs. Family caregivers, of patients randomized to the SCC, were expected to have lower risk of cardiovascular disease when compared to family caregivers, of patients randomized to SC. Methods: Of the 459 patients and 211 caregivers enrolled in this trial, patients’ mean age was 66 years, the majority were female (56.2%) and Caucasian (92.6%). Family caregivers had a mean age of 62 years, the majority were female (69%) and Caucasian (87%). Patients were screened for clinical levels of depression, pain, and/or fatigue and then were randomized to the SCC intervention or SC arm (referral to a community provider for treatment). Family caregivers were administered questionnaires and provided blood and anthropometric data to assess risk of CVD using the ASCVD calculator. Family caregivers did not receive the intervention. Health care utilization was collected from the patients' medical record and activity-based costs were used to assess health care savings. Intent to treat analyses using general linear mixed models were employed to test the hypotheses. Results: General linear mixed models revealed an interaction of quadratic time by arm effect with patients who were randomized to the SCC intervention having greater 0-to-6-month improvement in overall QoL versus patients randomized to the SC arm [t(579) = 2.23, p = .0259]. No group difference was observed in 6-to-12 month change in QoL suggesting maintenance of gains were observed at 12 months [t(561) = -1.34, p > .10]. Multivariate analyses showed a similar pattern of more rapid gains in the subscales of QoL at 6-months in the patients randomized to the SCC intervention when compared to patients in the SC arm on the emotional well-being [t(1,856) = 2.27, p = 0.012], functional well-being [t(1, 891) = 1.73, p = 0.042]; and physical well-being subscales [t(1,777) = 1.84, p = 0.033]. Family caregivers, of patients who were randomly assigned to the SCC intervention, had lower lifetime cardiovascular risk, when compared family caregivers of patients who were randomized to the SC (uMVχ²=9.00, p = 0.027). Activity based costs savings of $12,546 per patient per year in activity-based costs were observed for patients randomized to the SCC intervention versus SC. The drivers of the activity-based cost savings appear to be reductions in complication and readmission rates. Conclusions: Cancer centers, and payors, interested in novel delivery and payment models may consider this integrated strategy to improve patient quality of life and save health care costs. Clinical trial information: NCT02944136.