The objective was to examine co-occurrence of iatrogenic events in US hospitals. Using Agency for Healthcare Research and Quality patient safety indicators (PSIs), the authors defined multiple patient safety events (MPSEs) as the occurrence of multiple PSIs during a single hospitalization. The National Inpatient Sample was analyzed to estimate the national prevalence of MPSEs, risk factors for MPSEs, and the average length of stay and average hospital charges associated with MPSEs. MPSEs occurred in approximately 1 in every 1000 hospitalizations, affecting more than 30 000 patients in 2004. Significant risk factors for MPSEs include age, black race, Medicare coverage, and treatment at urban teaching hospitals. Compared with all admissions, the average length of stay for MPSE admissions was 4 times longer, and the average charge for MPSE admissions was 8 times greater. Despite the low prevalence, MPSEs affect large numbers of hospital patients in America. MPSEs have distinct characteristics and are far more resource intensive than hospital admissions generally.