Maximizing the impact of HIV pre-exposure prophylaxis (PrEP) requires optimizing access and adherence for those at risk of contracting HIV. This study examined challenges to the processes of accessing and adhering to PrEP encountered by participants from a large, U.S. urban clinical center and assessed the utility of objectively monitoring PrEP adherence via urine. Most participants (65%) reported starting PrEP within 1-3 months of hearing about it, although 35% of participants encountered a provider unwilling to prescribe PrEP. Self-reported adherence was high among this population, with remembering to take the medication reported as the major barrier to adherence (44%) rather than cost or stigma. Urine tenofovir (TFV) monitoring was highly acceptable to this population, and participants indicated greater willingness to undergo urine monitoring every 3 months compared to finger prick (dried blood spot), phlebotomy, or hair follicle testing. These findings highlight the importance of focusing efforts toward reducing obstacles to PrEP use and support the use of urine TFV adherence monitoring as a marker of PrEP adherence.