Fatigue while driving is one of the risk factors of road crashes. It's still poorly considered in interventions because of insufficient literature. In addition, the literature on this issue doesn't focus on two-wheelers, the most frequent users in the Benin context. The study examined the prevalence of fatigue while driving among two-wheeled vehicle drivers and the related factors. It's a secondary baseline data analysis from a cohort of road crash victims recruited from five hospitals in Benin. Data were collected from July 2019 to January 2020. Patients who identified themselves as drivers during the accident were included. Data on individual characteristics, including fatigue status in the moments preceding the collision, and other risk factors and environmental settings, were extracted. We used multivariate logistic regression. Among the respondents, 12.20% (95% CI=10.20-14.53) reported fatigue in the moments preceding the collision. The odds of fatigue while driving were significantly higher in male drivers (aOR=3.60; 95% CI=1.08-11.98), during professional trips (aOR=2.09; 95% CI=1.30-3.37), in non-helmet wearers (aOR=1.85; 95% CI=1.09-3.13), in users of stimulants (aOR=3.13; 95% CI=1.50-6.54), in those with a history of chronic diseases (aOR=1.95; 95% CI=1.16-3.27), at dusk (aOR=4.22; 95% CI=2.22-8.02), at night (aOR=6.90; 95% CI=3.95-12.05), and on Inter-State National Roads (aOR=2.01; 95% CI=1.18-3.43). Fatigue is a risk factor for road crashes in Benin, associated with other risk factors that highlight particularly vulnerable profiles and groups. Integrating prevention policies based on these cumulative risk factors will result in efficiency improvements.