The World Health Organization recently advocated a two-stage strategy with human papillomavirus (HPV) testing followed by visual inspection of the cervix with acetic acid (VIA) as a suitable option for cervical cancer screening. However, its accuracy has never been directly assessed in the context of primary screening. To evaluate effectiveness of HPV testing on self-obtained specimens (self-HPV) followed by VIA (sequential testing) in a low-income setting, we recruited 540 women aged between 30 and 65 years in two Cameroonian periurban areas. Eligible women were counseled about cervical cancer and how to perform self-sampling. HPV positive and a random sample of HPV-negative women were called back for VIA and biopsy. Disease was defined by interpretation of cervical intraepithelial neoplasia Grade 2 or worse (CIN2+). Performances of VIA, self-HPV and sequential testing were determined after adjustment for verification bias. HPV prevalence was 27.0%. VIA positivity was 12.9% and disease prevalence was 5%. Sensitivity and specificity of VIA for CIN2+ were 36.4% [95% confidence interval (CI): 15.2-64.6%] and 90.4% (95% CI: 85.4-93.7%), respectively. Sensitivity of self-HPV [100.0% (95% CI: 79.6-100.0%)] was 66% higher than that of sequential testing [33.3% (95% CI: 15.2-58.3%)]. Meanwhile, specificity of self-HPV [74.5% (95% CI: 70.6-78.1%)] was 22% lower than that of sequential testing [96.7% (95% CI: 94.8-97.9%)]. A two-stage screening strategy with self-HPV followed by VIA improves specificity of cervical cancer screening, but at the cost of an important loss of sensitivity. Ways to improve VIA performance or other tools are needed to increase positive predictive value of HPV testing.