This study sought to determine the academic and professional outcomes of medical school graduates who failed the United States Licensing Examination Step 1 on the first attempt. This retrospective cohort study was based on pooled data from 2,003 graduates of six Midwestern medical schools in the classes of 1997-2002. Demographic, academic, and career characteristics of graduates who failed Step 1 on the first attempt were compared to graduates who initially passed. Fifty medical school graduates (2.5 %) initially failed Step 1. Compared to graduates who initially passed Step 1, a higher proportion of graduates who initially failed Step 1 became primary care physicians (26/49 [53 %] vs. 766/1,870 [40.9 %]), were more likely at graduation to report intent to practice in underserved areas (28/50 [56 %] vs. 419/1,939 [ 21.6 %]), and more likely to take 5 or more years to graduate (11/50 [22.0 %] vs. 79/1,953 [4.0 %]). The relative risk of first attempt Step 1 failure for medical school graduates was 13.4 for African Americans, 7.4 for Latinos, 3.6 for matriculants >22 years of age, 3.2 for women, and 2.3 for first generation college graduates. The relative risk of not being specialty board certified for those graduates who initially failed Step 1 was 2.2. Our observations regarding characteristics of graduates in our study cohort who initially failed Step 1 can inform efforts by medical schools to identify and assist students who are at particular risk of failing Step 1.