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BackgroundOver 20 million people in the U.S. are behind on cervical cancer screenings (CCS). Sexual minority populations are 50% less likely to engage in routine screening, putting them at higher risk for cervical dysplasia and cancer due to undetected precancer and delayed diagnosis. Their barriers to speculum exams include access to care, sexual trauma, and provider bias. At-home HPV self-collection (SC) offers a clinically accurate, preferred alternative screening method.ObjectiveTo assess clinical agreement, usability, and screening experiences and preferences for an FDA-authorized at-home vaginal SC device among participants who identify as lesbian, gay, bisexual, pansexual, queer, or other non-heterosexual identities (LGBQ+).MethodsSELF-CERV was a prospective, multi-site method-comparison study conducted across 16 U.S. sites. Participants completed SC in a simulated at-home setting and underwent clinician collection with a speculum and cervical brush; paired specimens were tested for primary HPV using the Roche cobas. Surveys assessed barriers to screening, prior screening experiences, usability, and preferences. 609 participants were enrolled; 599 had paired samples, including 74 LGBQ+ participants.ResultsCompared with heterosexual participants, LGBQ+ participants more frequently delayed or avoided screening, had lower preventive care engagement, and described worse prior speculum-based screening experiences, including higher pain, discomfort, and aversion. Clinical agreement between self- and clinician-collected specimens was comparable, with no unanticipated safety concerns. The SC device was rated as easy to use and acceptable across groups; LGBQ+ participants reported greater comfort and empowerment and a stronger preference for at-home self-collection. Qualitative comments emphasized privacy and reduced distress, including trauma- and dysphoria-related concerns.ConclusionAt-home SC is a clinically valid, usable, and strongly preferred CCS option, particularly among LGBQ+ populations who experience disproportionate barriers to speculum-based CCS. Broader adoption of FDA-authorized at-home SC paired with telehealth will enable future impact assessment to reduce persistent disparities in CCS for LGBQ+ populations.