Fatigue has been linked to adverse safety outcomes, and poor quality or decreased sleep has been associated with obesity (higher body mass index, BMI). Additionally, higher BMI is related to an increased risk for injury; however, it is unclear whether BMI modifies the effect of short sleep or has an independent effect on work-related injury risk. To answer this question, the authors examined the risk of a work-related injury as a function of total daily sleep time and BMI using the US National Health Interview Survey (NHIS). The NHIS is an in-person household survey using a multistage, stratified, clustered sample design representing the US civilian population. Data were pooled for the 7-yr survey period from 2004 to 2010 for 101 891 "employed" adult subjects (51.7%; 41.1 ± yrs of age [mean ± SEM]) with data on both sleep and BMI. Weighted annualized work-related injury rates were estimated across a priori defined categories of BMI: healthy weight (BMI: <25), overweight (BMI: 25-29.99), and obese (BMI: ≥30) and also categories of usual daily sleep duration: <6, 6-6.99, 7-7.99, 8-8.99, and ≥9 h. To account for the complex sampling design, including stratification, clustering, and unequal weighting, weighted multiple logistic regression was used to estimate the risk of a work-related injury. The initial model examined the interaction among daily sleep duration and BMI, controlling for weekly working hours, age, sex, race/ethnicity, education, type of pay, industry, and occupation. No significant interaction was found between usual daily sleep duration and BMI (p = .72); thus, the interaction term of the final logistic model included these two variables as independent predictors of injury, along with the aforementioned covariates. Statistically significant covariates (p ≤ .05) included age, sex, weekly work hours, occupation, and if the worker was paid hourly. The lowest categories of usual sleep duration (<6 and 6-6.9 h) showed significantly (p ≤ .05) elevated injury risks than the referent category (7-8 h sleep), whereas sleeping >7-8 h did not significantly elevate risk. The adjusted injury risk odds ratio (OR) for a worker with a usual daily sleep of <6 h was 1.86 (95% confidence interval [CI]: 1.37-2.52), and for 6-6.9 h it was 1.46 (95% CI: 1.18-1.80). With regards to BMI, the adjusted injury risk OR comparing workers who were obese (BMI: ≥30) to healthy weight workers (BMI: <25) was 1.34 (95% CI: 1.09-1.66), whereas the risk in comparing overweight workers (BMI: 25-29.99) to healthy weight risk was elevated, but not statistically significant (OR = 1.08; 95% CI: .88-1.33). These results from a large representative sample of US workers suggest increase in work-related injury risk for reduced sleep regardless of worker's body mass. However, being an overweight worker also increases work-injury risk regardless of usual daily sleep duration. The independent additive risk of these factors on work-related injury suggests a substantial, but at least partially preventable, risk.