Background: Older patients with advanced cancer face considerable uncertainty related to their disease and treatment. The aim of our study was to evaluate the associations of uncertainty with psychological status and QoL. Methods: This is a secondary analysis of baseline data from a national geriatric assessment (GA) cluster randomized trial (URCC 13070; PI: Mohile). Patients aged ≥70 years with ≥1 GA domain impairment (e.g., function, cognition) and advanced cancer who were considering or receiving any line of cancer treatment were enrolled (n=541). Uncertainty was measured using the modified 9-item Mishel Uncertainty in Illness (MUIS), where respondents with higher scores perceive more uncertainty (range 9-45). QoL and psychological measures consisted of Functional Assessment of Cancer Therapy-General (FACT-G), emotional wellbeing (EWB; FACT-G subscale), distress (distress thermometer), anxiety (Generalized Anxiety Disorder-7), and depression (Geriatric Depression Scale-15). Multiple linear regressions were used to evaluate the associations of MUIS scores with each measure, adjusted for demographics, cancer type, and number of impaired GA domains. Results: Mean age was 77 years (SD 5, range 70-96); 26% had gastrointestinal cancer and 26% had lung cancer. Mean number of GA domain impairments was 4 (SD 1, range 1-7). Mean MUIS score was 20 (SD 5, range 9-37). On multivariate analyses, higher MUIS score was associated with lower QoL (β=-1.08, SE=0.11) and EWB (β=-0.29, SE=0.03), as well as higher distress (β=0.12, SE=0.02), anxiety (β=0.11, SE=0.04), and depression (β=0.09, SE=0.03; all P<0.01). Conclusions: Distress associated with uncertainty was common in a vulnerable population of frail older patients with advanced cancer and ≥1 GA domain impairment. A higher degree of uncertainty was associated with poorer psychological health and QoL. Our results underscore the important role that uncertainty plays in older patients' psychological status. Previous tested uncertainty management interventions (mainly including information and coping strategies) could be revised, tailored and tested to meet the unique needs of older patients with cancer. Clinical trial information: NCT02107443