This study aimed to gain a better understanding of the association between participation in a blinded antiretroviral pre-exposure prophylaxis (PrEP) clinical trial and sexual practices among men who have sex with men and transgender women. This study utilized both quantitative and qualitative methodologies. Data included reported PrEP medication adherence and sexual behavior among 114 study participants. Forty-six participants took part in qualitative data collection, 32 were interviewed and 14 participated in one of three focus group discussions. The average percentage of study medication adherence, number of sex partners and rates of sex without a condom were calculated. For qualitative data, content analysis was used to identify repeated normative themes, some of which arose spontaneously from interview interactions. Participants at the Chiang Mai site reported good adherence to the study medication. The sexual risk behavior of these participants had decreased by their final study visit; this was unrelated to level of adherence. Qualitative findings describe sexual practices that were highly contextual; participants used risk assessments to determine sex practices. Condoms were used with casual partners but not necessarily with primary partners. Our findings suggest that while PrEP is an exciting new development for HIV prevention, it must be paired with behavioral interventions to fully address sexual risk among this population. Interventions should provide this population with skills to negotiate condom use with their primary partners as well as in situations in which their sexual partners do not support condom use.