Music may be an effective therapeutic tool during cancer treatments to improve patient psychological and physical well-being. Patients receiving outpatient chemotherapy treatment often experience high levels of distress, and many have few, if any, nonpharmacological resources to aid in coping with pain, mood, and distress during often lengthy infusion treatments. Current research shows a positive effect of music on psychological outcomes; however, many of these studies lacked significant sample size as well as rigor in monitoring type of music content used and duration of music use during treatment. This study is an open-label, multi-center, day-based permuted block randomization study of 750 cancer patients that was designed to fill these gaps in the literature on receptive self-guided music therapy during chemotherapy with a large sample size and assessment of musical content and duration in relation to patient pain, positive and negative mood, and distress. Results showed that listening to self-selected music for periods up to 60 minutes during infusion showed a clinical benefit in improving positive mood and reducing negative mood and distress although not pain. Other findings suggest that there may be selective benefit of music for some patients based on relationship and employment status. These findings demonstrate music therapy is a low-touch, cost effective way to manage patients’ psychological well-being in the fast-paced and often stressful context of a cancer infusion clinic.