BACKGROUND In recent years, there has been an increasing interest in performing research on drug use and sex work among at-risk women. Although there is a well-documented literature of the initial reasons associated with drug use and sex work among women, there is, however, a paucity of information in this area in Iran. OBJECTIVES This study aimed to explore the initial reasons associated with drug use and sex work in a group of female treatment seekers, who presented health-related risk behaviors, in Tehran, Iran. PATIENTS AND METHODS This qualitative study enrolled a total of 65 at-risk women, from five women-specific drug clinics, who participated in the study in 2011. Individual in-depth interviews were conducted. Focus group interviews were conducted with 10 key informants. All interviews were audio-taped and thematically written. The recorded data were analyzed using ATLASti qualitative research software version 10. RESULTS The median age of the sample was 34 years. In addition, 44.6% of subjects were opiate users, and 55.4% were users of opiates and methamphetamine. Sex work was the main source of income for almost half of the sample. The most frequently reported reasons, associated with initial drug use, were extrinsic motivations, including the drug-using family, friends or social networks. Intrinsic motivations, including curiosity and individual willingness to use drugs, were other initial reasons. The most frequently reported reasons, associated with initial sex work, included the need to purchase drugs and financial problems. CONCLUSIONS The study findings demonstrated a number of reasons associated with initial drug use and sex work. The role of sex work in providing drugs necessitates education and prevention. Special treatment programs should be implemented to prevent sex work among at-risk women in Iran.