Background: Prostitution and substance abuse are among the crucial social problems in women, which affect the quality of life. However, no study has yet investigated that prostitution and substance abuse affect which dimension(s) of quality of life. The current study aimed to compare different dimensions of quality of life among female sex workers with and without drug abuse. Methods: The research design was ex post facto study. The study sample comprised 120 women (60 female sex workers with substance abuse and 60 without substance abuse). They were selected through convenience sampling method in Tehran, in 2016. They completed WHO Quality of Life-BREF questionnaire. Data analysis was done using multivariate analysis of variance and covariance methods by SPSS V. 20. Results: According to the results, there was a significant difference between female sex workers with and without drug use (P < 0.05) with regard to physical, social relationship and environment health. The sex workers without drug abuse had higher quality of life in aforementioned aspects. However, no significant difference was observed among two groups with regard to psychological health (P > 0.05). Conclusion: The results indicated that quality of life in female sex workers with using drug is poorer than their counterparts who are not drug users. These findings emphasize that health care providers can consider quality of life as an essential factor in therapeutic intervention (primary and secondary) in prostitutes and addicted women. Female sex workers using drug have the psychological, social, and biological needs that require the immediate and considerable attention.