The recent successes of biomedical HIV prevention approaches have sparked considerable debate over the scalability, feasibility, and acceptability of pre-exposure prophylaxis (PrEP) as a widespread prevention strategy for men who have sex with men and trans-gender. Anticipated difficulties with PrEP adherence and concerns about resources required to best support it have tempered enthusiasm of PrEP demonstration projects and roll-out. While no evidence-based approach for supporting PrEP use is presently available, a number of approaches have been developed in the context of double-blind, randomized, placebo-controlled trials of PrEP that can provide guidance in moving forward with real world support of open label PrEP use. We present the development, implementation and evaluation of feasibility and acceptability of next-step counseling (NSC) and neutral assessment (NA), the adherence support and promotion of accurate reporting approaches used in the late phases of the iPrEx study. Evaluation of the approach from the perspective of implementers of over 15,000 NSC sessions in seven different countries with almost 2,000 iPrEx participants provided support for NSC, its brevity (averaging ~14 min per follow-up session) and overall acceptability and feasibility. NA also was generally well supported, with a majority of study staff believing this approach was feasible and acceptable; however, lower acceptability for certain aspects of NA was noted amongst staff reporting NA was different from their previous interview approach. Quantitative and qualitative data gathered from implementers were used to make modifications for supporting PrEP use in the open-label extension of iPrEx.