Background <p>High-risk human papillomavirus (HR-HPV) is the leading cause of cervical cancer. Screening is one of the main cornerstones of cervical cancer prevention. Self-sampling for HR-HPV is introduced to improve patient involvement in the screening program. The study aimed to understand the hesitancy and barriers to self-sampling among high-risk women who are at risk of developing cervical cancer.</p> Methods <p>This qualitative study employed semi-structured telephone interviews to explore the factors behind the refusal of HR-HPV self-sampling among twelve purposefully selected women (aged 25-49) with abnormal Pap smears recruited from a colposcopy clinic within a major urban university hospital in Riga, Latvia. The interviews, conducted between June and September 2022, were transcribed verbatim and subjected to inductive content analysis.</p> Results <p>Four inductive categories were developed and described: (1) 'Clinic visit–related distress' described patients’ situational anxiety, fears, and during the visit to a healthcare facility that resulted in the refusal to take the HR-HPV self-sampling; (2) ‘Health literacy challenges’ highlighted patients' lack of knowledge and understanding of cervical cancer causation and screening role in the early detection of cervical cancer; (3) ‘Doctor does and knows the best’ explored patients' doubts and fears about the accuracy and comparability of HR-HPV self-sampling with conventional screening methods; (4) ‘Circumstances that can promote taking the HR-HPV self-sampling’ illuminated the circumstances that can encourage women to take the HR-HPV self-sampling.</p> Conclusions <p>A complex interplay of contextual factors contributed to the hesitancy of HR-HPV self-sampling in the group of women at high risk for cervical cancer, highlighting that women's decision-making regarding this procedure goes beyond its purely clinical aspects.</p>