Pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) are highly efficacious biomedical prevention strategies, which significantly reduce the risk of HIV transmission. Yet, partnered sexual minority men (SMM) continue to exhibit poorer uptake rates especially those in a non-monogamous or serodiscordant relationship for whom PrEP is recommended. The purpose of the study was to identify factors that may facilitate or impede the uptake of PrEP or PEP among partnered SMM. This qualitative study conducted semi-structured interviews with 10 sexual minority male couples recruited from the New York City metropolitan area. Thematic analysis identified relationship-specific and structural-level factors, which influence motivation and willingness for biomedical prevention uptake. Specifically, results highlighted the tension between relationship functioning and HIV prevention. In addition, stigma and access to knowledgeable health care providers diminished interest in biomedical prevention. Findings suggest a need for interventions that frame biomedical prevention in ways that minimize social perceptions of mistrust between partners and improve access.