Aim: To explore the prevalence, phenomenology, and background of leisure sickness, i.e., the condition of people developing symptoms of sickness during weekends and/or vacations. Method: In order to obtain an estimate of its prevalence, a representative Dutch sample consisting of 1,128 men and 765 women was asked to indicate to what extent they recognized themselves in our description of weekend and vacation sickness. For the investigation of the phenomenology and background of this condition and the characteristics of the patients suffering from it, questionnaire data were collected in new samples consisting of 114 cases and 56 controls. Questions referred to symptoms, onset, duration, appreciation of weekend and vacation activities, and appraisal of work and workload. Results: In the case of male respondents, 3.6 and 3.2% recognized themselves in the description of the weekend and the vacation syndrome, respectively, compared with 2.7 and 3.2% women. Most frequently reported symptoms were headache/migraine, fatigue, muscular pains, and nausea. In addition, viral infections (flue-like, common cold) were often reported in relation to vacations. Cases had generally suffered from leisure sickness for over 10 years and the onset was associated with stressful conditions. They attributed their condition to difficulties with the transition from work to nonwork, stress associated with travel and vacation, as well as workload and personality characteristics. There were no significant group differences in the appreciation of weekend and leisure activities or lifestyle during days off. Most striking differences were found with respect to experienced workload, sense of responsibility, and inability to relax. Conclusion: Leisure sickness is a relatively common condition. Specific lifestyle factors or leisure activities seem to be less relevant for its development. Concerning risk factors, the data tend to point to high workload and person characteristics, namely, the inability to adapt to the nonworking situation, a high need for achievement, and a high sense of responsibility with respect to work. Future studies should be designed for testing specific hypotheses concerning the underlying mechanisms and evaluating the effectiveness of psychological and/or physical activity interventions.