Catastrophic medical malpractice payouts, $1 million or greater, greatly influence physicians’ practice, hospital policy, and discussions of healthcare reform. However, little is known about the specific characteristics and overall cost burden of these payouts. We reviewed all paid malpractice claims nationwide using the National Practitioner Data Bank over a 7-year period (2004–2010) and used multivariate regression to identify risk factors for catastrophic and increased overall payouts. Claims with catastrophic payouts represented 7.9% (6,130/77,621) of all paid claims. Factors most associated with catastrophic payouts were patient age less than 1 year; quadriplegia, brain damage, or lifelong care; and anesthesia allegation group. Compared with court judgments, settlement was associated with decreased odds of a catastrophic payout (odds ratio, 0.31; 95% confidence interval [CI], 0.22–0.42) and lower estimated average payouts ($124,863; 95% CI, $101,509–144,992). A physician's years in practice and previous paid claims history had no effect on the odds of a catastrophic payout. Catastrophic payouts averaged $1.4 billion per year or 0.05% of the National Health Expenditures. Preventing catastrophic malpractice payouts should be only one aspect of comprehensive patient safety and quality improvement strategies. Future studies should evaluate the benefits of targeted interventions based on specific patient safety event characteristics.