Background: To date, numbers of studies have indicated the important role of fine manual dexterity in typical and special populations. However, the relevant studies in Down's syndrome (DS) population is still limited. The purpose of this study was to investigate the determinants of manual dexterity in adolescents and young adults with DS. Methods: Thirty participants with DS (22 males, 8 females, aged 13-31) were screened by anthropometric variables (i.e. sex, chronological age, verbal intelligence, body mass index), levels of physical activity, and sleep disorders, and were administered the Purdue Pegboard Test and the Choice Reaction Time Test. Measures of correlation, t-test and multiple regression model were used for data analysis. Results: It was indicated that sex and sleep-related disorders during the day explained 37.2% of the variance in the performance of the Purdue Pegboard Test. The additional of 9.7% can be explained the variance by adding reaction time test performance. Verbal intelligence had the negatively relation with the performance of non-Dominant Hand and Bimanual subtests of the Purdue Pegboard Test. Conclusion: This study suggested that sex, sleep disorder, and neuromotor function may be the important determinants of fine manual dexterity performance in adolescents and young adults with DS. In addition, the level of intelligence might also exert the effect on fine motor development in this population. In order to design effective interventions and optimize manual performance in individuals with DS, these possible determinants should be considered. Future research should be replicated with large sample size, different age groups, and validated measures of finger size, physical activity and sleep behaviors.