Introduction: Studies have reported associations between obesity and injury in a single occupation or industry. Our study estimated the prevalence of work-site injuries and investigated the association between obesity and work-site injury in a nationally representative sample of U.S. workers. Methods: Self-reported weight, height, and injuries within the previous three months were collected annually for U.S. workers in the National Health Interview Survey (NHIS) from 2004-2012. Participants were categorized as normal weight (BMI: 18.5-24.9 kg/m2), overweight (BMI: 25.0-29.9), obese I (BMI: 30.0-34.9), and obese II (BMI: 35 +). The prevalence of injury and prevalence ratios from fitted logistic regression models was used to assess relationships between obesity and injury after adjusting for covariates. Sampling weights were incorporated using SUDAAN software. Results: During the 9-year study period from 2004 to 2012, 1120 workers (78 workers per 10,000) experienced a work-related injury during the previous three months. The anatomical sites with the highest prevalence of injury were the back (14.3/10,000 ± 1.2), fingers (11.5 ± 1.3), and knees (7.1 ± 0.8). The most common types of injuries were sprains/strains/twists (41.5% of all injuries), cuts (20.0%), and fractures (11.8%). Compared to normal weight workers, overweight and obese workers were more likely to experience work-site injuries [overweight: PR = 1.25 (95% CI = 1.04-1.52); obese I: 1.41 (1.14-1.74); obese II: 1.68 (1.32-2.14)]. These injuries were more likely to affect the lower extremities [overweight: PR = 1.48, (95% CI = 1.03-2.13); obese I: 1.70 (1.13-2.55); obese II: 2.91 (1.91-4.41)] and were more likely to be due to sprains/strains/twists [overweight: PR = 1.73 (95% CI = 1.29-2.31); obese I: PR = 2.24 (1.64-3.06); obese II: PR = 2.95 (2.04-4.26)]. Conclusions: Among NHIS participants, overweight and obese workers were 25% to 68% more likely to experience injuries than normal weight workers. Practical applications: Weight reduction policies and management programs may be effectively targeted towards overweight and obese groups to prevent or reduce work-site injuries.