Limited data exist regarding attitudes and acceptability of topical and oral HIV pre-exposure prophylaxis (PrEP) among US black women. This investigation explored interest in HIV chemoprophylaxis and modes of use. Five focus groups enrolled 26 black women recruited from an inner-city community health center and affiliated HIV testing sites. Thematic analysis utilized Atlas.ti. Most women expressed interest in PrEP, as many reported condom failure concerns. Most women preferred a pill formulation to intravaginal gel because of greater perceived privacy and concerns about vaginal side effects and gel leakage. Women who had taken pills previously advocated daily dosing and indicated adherence concerns about episodic or post-coital PrEP. Many women desired prophylactic strategies that included partner testing. Urban black women are interested in utilizing PrEP; however, misgivings exist about gel inconvenience and potential side effects for themselves and their partners. Most women preferred oral PrEP, dosed daily.