A high proportion of U.S. health care costs are attributable to a relatively small proportion of patients. Understanding behavioral and social factors that predict initial and persistent high costs for these “high utilizers” is critical for health policy-makers. This prospective observational study was conducted at Kaiser Permanente Northern California (KPNC), an integrated healthcare delivery system with 4.1 million members. A stratified random sample of high-cost vs. non-high-cost adult KPNC members matched by age, gender, race/ethnicity, type of health insurance, and medical severity (N = 378) was interviewed between 3/14/2013 and 3/20/2014. Data on health care costs and clinical diagnoses between 1/1/2008 and 12/31/2012 were derived from the electronic health record (EHR). Social-economic status, depression symptoms, adverse childhood experiences (ACEs), interpersonal violence, financial stressors, neighborhood environment, transportation access, and patient activation and engagement were obtained through telephone interviews. Initial and subsequent high-cost status were defined as being classified in top 20% cost levels over 1/1/2009-12/31/2011 and 1/1/2012-12/31/2012, respectively. Psychiatric diagnosis (OR 2.55, 95% CI 1.52-4.29, p < 0.001), financial stressors (OR 1.97, 95% CI 1.19-3.26, p = 0.009), and ACEs (OR 1.10, 95% CI 1.00-1.20, p = 0.051) predicted initial high-cost status. ACEs alone predicted persistent high-cost status in the subsequent year (OR 1.12, 95% CI 1.00-1.25, p = 0.050). Non-medical factors such as psychiatric problems, financial stressors and adverse childhood experiences contribute significantly to the likelihood of high medical utilization and cost. Efforts to predict and reduce high utilization must include measuring and potentially addressing these factors.