Background: Onchocerciasis is targeted for elimination with annual community-directed treatment with ivermectin (CDTi). High infection levels were reported in South-West Cameroon, despite ≥ 15 years of CDTi. Methods: A large-scale cross-sectional study was conducted in 2017 in 20 communities in a loiasis-risk area in South-West Cameroon. A mixed-methods approach was used to evaluate factors associated with continued transmission and skin disease. Associations between infection levels, skin disease and adherence to CDTi were assessed using mixed regression modelling. Different community members’ perception and acceptability of the CDTi strategy was explored using semi-structured interviews. Results: Onchocerciasis prevalence was 44·4% among 9,456 participants. 5·9% of adults participated in ≥ 75% of CDTi rounds and 17·5% were systematic non-adherers. Skin disease affected 1/10 participants, including children. Increasing self-reported adherence to CDTi was associated with lower infection levels in participants aged ≥ 15 years but not in children. Adherence to CDTi was negatively influenced by fear of adverse events linked with economic loss and concern of lethal adverse events, and positively influenced by perceived health benefits. Interpretation: High onchocerciasis prevalence and morbidity still occur in South-West Cameroon, including among children born in the CDTi era. Because non-adherence is mostly due to community perception of ivermectin-related adverse events, including death and lack of perceived health benefit, CDTi alone is unlikely to achieve elimination in this area of high transmission. Alternative strategies are needed for onchocerciasis elimination where negative perception of ivermectin is an entrenched barrier to community participation in programmes. Funding Statement: Department for International Development, UK. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This protocol was reviewed and approved by the Liverpool School of Tropical Medicine Research Ethics Committee (reference: 16-027), the Cameroonian National Ethics Committee for Research on Human Health (approval no. 2016/11/838/CE/CNERSH/SP), and the Division of Health Operations Research within the Cameroonian Ministry of Public Health (approval no. 631-03·17). All censused individuals were explained the objectives and procedures of the intervention study. Informed assent was obtained from children and adolescents aged under 18 years with parental consent, and consent was provided by all adult participants.