Background and objectives: Chronic kidney disease (CKD) lacks standardized patient safety indicators (PSIs); however, undetected safety events are likely to contribute to adverse outcomes in this disease. This study sought to determine the proportion of CKD patients who experience multiple potentially hazardous events from varied causes and to identify risk factors for the occurrence of "multiple hits." Design, setting, participants, & measurements: A sample of patients with CKD (n = 70,154) in the Veterans Health Administration (VHA) were retrospectively examined for the occurrence of one or more safety events from a set of indicators defined a priori, including Agency for Healthcare Research and Quality (AHRQ) PSIs, hypoglycemia, hyperkalemia, and dosing for selected medications not accounting for CKD. Results: Approximately half of the cohort participants experienced one or two adverse safety events, whereas 7% had three or four (multiple) distinct events. Individuals with three or four of the predesignated safety events were more likely to be diabetic, non-Caucasian, have an estimated GFR (eGFR) < 30 ml/min/1.73 m2, and be ≤65 yr of age. A "Safety Risk Index" was developed using these characteristics, and those subjects that had all four traits were 25 times as likely to have three or four adverse safety events versus those with none of the characteristics. Conclusions: Patients with CKD are at a high risk for safety events pertinent to this disease and a substantial number are subject to multiple events from a diverse set of safety indicators, which could have important consequences in disease outcomes. Copyright © 2010 by the American Society of Nephrology.