PURPOSE: More than half of individuals with serious mental illness (SMI) smoke, contributing to premature cancer mortality. A cancer diagnosis provides an opportunity to assist with smoking cessation; however, supportive oncology trials frequently exclude patients with SMI. To fill this gap, we examined differences in engagement and tobacco cessation in a pragmatic clinical trial. METHODS: We recruited 303 participants from two National Cancer Institute–designated Comprehensive Cancer Centers, of which 10% had prior diagnoses of SMI (major depressive disorder, bipolar disorder, and schizophrenia spectrum disorders). We compared self-reported smoking behaviors, patient attitudes and beliefs about cessation, and rates of trial completion, engagement, and smoking abstinence among recently diagnosed patients with cancer with and without SMI. Six months after trial completion, we completed qualitative interviews on barriers and facilitators to tobacco cessation in a random sample of participants with SMI. RESULTS: Trial participants with SMI had similar motivation to quit smoking as those without SMI. Additionally, participants with SMI had a similar ability to engage in a tobacco treatment trial (6.5 counseling sessions completed v 7.3 sessions) and benefit from tobacco treatment as those without SMI (32.3% v 27.8% 6-month quit rates). CONCLUSION: Patients with cancer and SMI were able to engage in and benefit from a tobacco cessation trial integrated into cancer care. A cancer diagnosis provides an opportunity to assist patients with SMI with smoking cessation referrals and treatment. Pragmatic supportive oncology trials that include a diverse population of adults with SMI are needed to inform care delivery and improve cancer outcomes for patients with SMI and cancer.