e23170 Background: Social isolation is a major public health concern due to its effects on morbidity and mortality in the general population. Emerging evidence suggests greater social isolation among individuals diagnosed with cancer, but there is limited understanding of its relationship with psychosocial functioning in cancer survivors. This study examined associations of social isolation and mental health, sleep quality, and health-related quality of life (HRQoL) among cancer survivors and age-matched controls in the Cancer Prevention Study-3 cohort. Methods: We included 4,137 cancer survivors and 12,411 controls who provided complete data for variables of interest on the 2018 survey. Social isolation was assessed on a 5-point scale by the Social Network Index, and classified as low (0-1), moderate (2), and high (3-4). Raw scores from the PROMIS Global Health Scale for HRQoL (10 items) and global mental health (GMH; 4 items) were converted to T-scores (higher score = better). Sleep quality was assessed by a single-item 4-point scale: 1 (very poor) to 4 (very well). ANCOVA analyses were adjusted for age, sex, BMI, education, smoking status, alcohol consumption, and physical activity (PA), as well as stratified by age, sex, and lifestyle factors. Results: Mean age of the population was 60 (34-77) years, 76% were female and 90% non-Hispanic White. Thirty-two percent of survivors and 30% of controls reported moderate to high levels of social isolation. Mean scores for sleep quality, GMH, and HRQoL were significantly lower among survivors vs. controls (all P ≤0.01). There were no significant cancer (yes/no) x social isolation interactions. Among all study participants, ANCOVAs showed that high (vs. low) social isolation was associated with poorer sleep quality (adjusted mean difference = 4%; effect size, ES = 0.14), worse GMH (adjusted mean difference = 12%; ES = 0.68), and lower HRQoL (adjusted mean difference = 8%; ES = 0.57; all Ptrend < 0.0001). Stratified analyses showed stronger associations between greater social isolation and lower HRQoL among females vs. males, less active ( < 15 MET-hr/wk) vs. more active (≥15 MET-hr/wk) participants, and infrequent (none/less than daily) vs. regular alcohol drinkers (≥1 drinks/day). The higher social isolation-lower GMH association was also stronger in females vs. males and less active vs. more active participants. The social isolation-sleep quality association was stronger among infrequent vs. regular alcohol drinkers. Conclusions: These results indicated that high social isolation is associated with poorer sleep quality, mental health, and health-related quality of life, independent of cancer diagnosis. Women and less active participants may be particularly at risk, suggesting that targeted interventions to reduce social isolation in these populations may be warranted. Support: The ACS funds the creation, maintenance, and updating of the CPS-3 cohort.