The Injury Severity Score (ISS) is a measure of injury severity widely used for research and quality assurance in trauma. Calculation of ISS requires chart abstraction, so it is often unavailable for patients cared for in nontrauma centers. Whether ISS can be accurately calculated from International Classification of Diseases, Ninth Revision (ICD-9) codes remains unclear. Our objective was to compare ISS derived from ICD-9 codes with those coded by trauma registrars. This was a retrospective study of patients entered into 9 U.S. trauma registries from January 2006 through December 2008. Two computer programs, ICDPIC and ICDMAP, were used to derive ISS from the ICD-9 codes in the registries. We compared derived ISS with ISS hand-coded by trained coders. There were 24,804 cases with a mortality rate of 3.9%. The median ISS derived by both ICDPIC (ISS-ICDPIC) and ICDMAP (ISS-ICDMAP) was 8 (interquartile range [IQR] = 4–13). The median ISS in the registry (ISS-registry) was 9 (IQR = 4–14). The median difference between either of the derived scores and ISS-registry was zero. However, the mean ISS derived by ICD-9 code mapping was lower than the hand-coded ISS in the registries (1.7 lower for ICDPIC, 95% CI [1.7, 1.8], Bland–Altman limits of agreement = −10.5 to 13.9; 1.8 lower for ICDMAP, 95% CI [1.7, 1.9], limits of agreement = −9.6 to 13.3). ICD-9-derived ISS slightly underestimated ISS compared with hand-coded scores. The 2 methods showed moderate to substantial agreement. Although hand-coded scores should be used when possible, ICD-9-derived scores may be useful in quality assurance and research when hand-coded scores are unavailable.