Daily oral pre-exposure prophylaxis is an effective strategy for HIV prevention; yet, uptake has been lower than anticipated. This study explores the factors that influenced current users’ decisions to initiate PrEP in Western New York. Qualitative data from 41 semi-structured interviews were thematically analyzed. Participants' decision to initiate PrEP was based on individual, interpersonal and structural factors. PrEP users initiated when there was an increase in knowledge, risk perception, sexual health communication, and PrEP access. Findings suggest for PrEP to maximize its HIV prevention potential, public health interventions that utilize a multi-level approach may be most impactful to increase uptake.