Few studies of pre-exposure prophylaxis (PrEP) to prevent HIV infection have focused on drug users. Between February to September 2013, we asked 351 opiate injectors entering detoxification treatment about HIV risk, knowledge about PrEP, and willingness to use a once daily PrEP pill under one of two randomly assigned effectiveness scenarios—40 % (low) or 90 % (high) effective in reducing HIV risk. Participants were 70 % male and 87 % non-Hispanic White. Only 7 % had heard of a drug to reduce HIV risk, yet once informed, 47 % would be willing to take such a pill [35 % of those in the low effectiveness scenario and 58 % in the high group (p < 0.001)]. Higher perceived HIV risk was associated with greater willingness to take medication. Increasing knowledge of PrEP and the rate of HIV reduction-effectiveness promised will influence its use among targeted high-risk drug users.