Objective: The authors compared the performance of a novel self-collect device with clinician-collected samples for detection of high-risk human papillomavirus (hrHPV)., Materials and Methods: Eighty-two (82) participants were recruited from 5 clinical sites in the United States. Each participant performed self-collect sampling using the self-collect device followed by a standard of care clinician-collected sample. Both samples were evaluated for hrHPV using polymerase chain reaction (PCR)-based HPV assays. A subset of HPV-positive samples underwent dual staining (p16/Ki-67), and concordance was evaluated. Biopsy results collected per standard of care were recorded., Results: On the Roche cobas assay, the preliminary positive percent agreement (PPA) and negative percent agreement (NPA) was 91%. Agreement for hrHPV using the BD OnClarity in PreservCyt was 100% PPA (n = 10), and 100% PPA, 93% NPA in SurePath. Dual-stain concordance was 93% (n = 16) overall, and 100% for HPV other genotypes. Seventy-one participants (n = 71; 89%) indicated they would feel confident using the self-collect device for screening if they knew they could get equal results, and 86% (n = 69) indicated that they would be more likely to get screened with this option., Conclusions: The self-collect device shows high (>92%) positive and negative agreement for detection of HPV when compared with reference clinician-collected samples, with very high acceptability and preference. Furthermore, the self-samples collected with the self-collect device showed highly concordant results by dual stain, which is a novel and emerging application for a self-collected sampling device, thus enabling potential triage from 1 sample., Competing Interests: Role of funding source: The study was funded by Teal Health, Inc, which is a biotechnology startup company. The funding source was involved in the study design, collection, analysis, and interpretation of data, as well as the writing of the report and decision to submit the article for publication. All authors have access to the data and take responsibility for the integrity of the data and accuracy of data analysis. All potential conflicts of interest have been disclosed. MBF is a current employee at Teal Health. No other relationships or activities have influenced the submitted work. The other authors have declared they have no conflicts of interest., (Copyright © 2024, ASCCP.)