PURPOSE Fatigue jeopardizes seafarer's health and safety. Thus, knowledge on determinants of fatigue is of great importance to facilitate its prevention. However, a systematic analysis and quality assessment of all empirical evidence specifically for fatigue are still lacking. The aim of the present article was therefore to systematically detect, analyze and assess the quality of this evidence. METHODS Systematic searches in ten databases were performed. Searches considered articles published in scholarly journals from 1980 to April 15, 2016. Nineteen out of 98 eligible studies were included in the review. The main reason for exclusion was fatigue not being the outcome variable. RESULTS Most evidence was available for work time-related factors suggesting that working nights was most fatiguing, that fatigue levels were higher toward the end of watch or shift, and that the 6-h on-6-h off watch system was the most fatiguing. Specific work demands and particularly the psychosocial work environment have received little attention, but preliminary evidence suggests that stress may be an important factor. A majority of 12 studies were evaluated as potentially having a high risk of bias. CONCLUSIONS Realistic countermeasures ought to be established, e.g., in terms of shared or split night shifts. As internal as well as external validity of many study findings was limited, the range of factors investigated was insufficient and few studies investigated more complex interactions between different factors, knowledge derived from studies of high methodological quality investigating different factors, including psychosocial work environments, are needed to support future preventive programs.