ObjectivesTo identify the risk factors associated with all medical encounters (MEs) and serious/life-threatening MEs (SLMEs) during the Comrades Marathon. DesignProspective cohort study, with cross-sectional analyses. MethodsDuring the 2014–2019 Comrades Marathon, all MEs (including SLMEs) were recorded in 103,131 starters. For both all MEs and SLMEs, the following risk factors were explored: sex, age, route (“up” vs. “down” race), previous Comrades experience (yes/no), wet-blub globe temperature (WBGT) and race pace. Incidence (per 1000 starters; 95%CI), and the incidence ratio (IR; 95%CI) are presented. ResultsFor all MEs, being female was a significant risk factor (females vs. males IR = 1.47, p < 0.0001), and age was only marginally significant (p = 0.0167). Therefore factors for all MEs were adjusted for sex. Other factors significantly associated with all MEs were: higher WBGT (highest WBGT compared to lowest, IR = 1.33, p = 0.0003), race pace (highest risk for those who finish either among the first quarter [IR = 1.49] or last quarter [IR = 1.46] compared to middle pace; p < 0.0001) and the route (“down” vs. “up”: IR = 1.11; p = 0.0181). Factors associated with higher risk for SLMEs were: females (IR = 1.9; p = 0.0003), “down” vs. “up” route (IR = 1.37; p = 0.0306) and race pace (slower and faster runners vs. mid (6.4–7.1 min/km) race pace category (IR > 2.1, p < 0.0001)). ConclusionsIntrinsic (female, faster and slower race pace) and extrinsic (higher WBGT and the “down” route) are novel risk factors associated with all MEs at this event. These can be considered by the race organizers and the medical team to develop and implement prevention strategies.