Abstract Background In Sweden, the cervical cancer screening programme is based on primary human papillomavirus (HPV) testing with either clinician-collected cervical sampling or home-based vaginal self-sampling. We assessed the effectiveness and cost-effectiveness of primary HPV clinician-collected sampling and primary HPV self-collected sampling for unvaccinated cohorts of Swedish women. Methods A model-based analysis was performed to project long-term costs and quality-adjusted life-years (QALYs). Screening strategies included no screening, 18 clinician-collected strategies and 36 self-sampling strategies, with variations in the screening frequency, start age and follow-up management. We estimated incremental cost-effectiveness ratios benchmarked against willingness-to-pay (WTP) thresholds of €50,000 and €100,000 per QALY gained. Results Compared with the 2022 recommendations (with primary clinician-collected HPV testing from ages 23 with 5-yearly screening to age 50 and 7-yearly screening through to age 64), self-sampling at the same intensity would lead to similar effectiveness and a 36% reduction in costs. Among the clinician-collected sampling strategies, the optimal strategies involved primary HPV testing from age 25 with 10-yearly screening with extended genotyping (at €50,000 per QALY gained), or 7- and 10-yearly screening for €100,000. Across all strategies, the optimal strategies included primary self-sampling from age 25 with direct referral to colposcopy for HPV-16/18/45 with 7- and 10-yearly screening at €50,000 per QALY gained, and 5- and 7-yearly screening for €100,000 per QALY gained. These results were sensitive to the assumed accuracy of self-sampling compared with clinician-collected sampling. Conclusions Transitioning from clinician-collected cervical sampling to vaginal HPV self-sampling is likely to be cost-effective for unvaccinated women in Sweden. Highlights - For an analysis restricted to clinician-collected sampling, the 2022 Swedish population-based recommendations (primary HPV testing from age 23 with 5-yearly screening to age 50 and 7-yearly screening between ages 50 and 64 years) were on the cost-efficiency frontier, however longer screening intervals were optimal. - For all of the considered strategies, the optimal strategies were primary vaginal self-sampling from age 25 years with direct referral to colposcopy for HPV 16, 18 and 45 with seven- and ten-yearly screening at €50,000 per QALY gained, and with five- and seven-yearly screening at €100,000 per QALY gained.