Exercise dependence (ED) is common in endurance athletes and can lead to physical and psychological distress with various health effects. We designed a prospective cross-sectional study to investigate the personality traits associated with ED among ultraendurance athletes. A total of 507 participants (41.6 (9.8) years, men: 73.7%) completed (1) a screening questionnaire about sociodemographic data, sporting habits, and healthcare data, (2) the Exercise Dependence Scale-Revised (EDS-R, 21 items scored from 1 (never) to 6 (always), 7 subscales), (3) the Big Five Inventory (BFI), and (4) 2 items of the SCOFF (Sick-Control-One Stone-Fat-Food) questionnaire regarding possible eating disorders. Based on the EDS-R scores, 37 (7.3%) participants were at risk for ED (scores ≥ 5/6 on ≥3 subscales), 366 (72.2%) were nondependent but symptomatic (scores ≥ 3/6 on ≥3 subscales), and 104 (20.5%) were asymptomatic. Participants with ED had a greater training volume and a higher prevalence of possible eating disorders. A higher level of neuroticism was associated with increased EDS-R scores (r = 0.294; p < 0.001), with significantly higher scores in the ED group (F = 14.50, p < 0.001). The association between neuroticism and ED was not moderated by the presence of eating disorders. These findings will help to screen ultraendurance athletes at risk for ED and optimize their care.