Global literature suggests that gatekeepers exert enormous influences on lives of female sex workers (FSWs). However, virtually no available studies have examined the FSW-gatekeeper relationship (F-G relationship) and its impact on FSW's mental health. The current study was conducted in 2008-2009 in two cities of southwest China. A total of 1022 FSW were recruited through community outreach from nine different types of commercial sex establishments. Both bivariate and multivariate analyses were employed to depict the association between F-G relationship and measures of FSW's mental health. Findings of the current study revealed that FSW with a close relationship with their gatekeepers reported a better mental health status. After adjusting for demographics and potential confounders of mental health, F-G relationship was positively associated with hopefulness ( β = .09, 95% CI = .01, .16), but negatively associated with perceived stigma ( β = -.25, 95% CI = -.44, -.07), suicidal intention or attempt (aOR = .90, 95% CI = .83, .99), and loneliness ( β = -.29, 95% CI = -.47, -.12). F-G relationship is an independent predictor of mental health of FSW over and above potential confounders including partner violence and substance use. Future health promotion programs targeting FSW need to recognize the role of gatekeepers in the life of FSW and engage them in a socially and legally acceptable way in safeguarding or improving mental health status of FSW in China.