BACKGROUND: Human papillomavirus (HPV) has proven to be the cause of several severe clinical conditions on the cervix, vulva, vagina, anus, oropharynx and penis. Several studies have assessed the costs of cervical lesions, cervical cancer (CC), and genital warts. However, few have been done in Africa and none in Swaziland. Cost analysis is critical in providing useful information for economic evaluations to guide policymakers concerned with the allocation of resources in order to reduce the disease burden. MATERIALS AND METHODS: A prevalence-based cost of illness (COI) methodology was used to investigate the economic burden of HPV-related diseases. We used a top-down approach for the cost associated with hospital care and a bottom-up approach to estimate the cost associated with outpatient and primary care. The current study was conducted from a provider perspective since the state bears the majority of the costs of screening and treatment in Swaziland. All identifiable direct medical costs were considered for cervical lesions, cervical cancer and genital warts, which were primary diagnoses during 2015. A mix of bottom up micro-costing ingredients approach and top-down approaches was used to collect data on costs. All costs were computed at the price level of 2015 and converted to dollars ($). RESULTS: The total annual estimated direct medical cost associated with screening, managing and treating cervical lesions, CC and genital warts in Swaziland was $16 million. The largest cost in the analysis was estimated for treatment of high-grade cervical lesions and cervical cancer representing 80% of the total cost ($12.6 million). Costs for screening only represented 5% of the total cost ($0.9 million). Treatment of genital warts represented 6% of the total cost ($1million). CONCLUSION: According to the cost estimations in this study, the economic burden of HPV-related cervical diseases and genital warts represents a major public health issue in Swaziland. Prevention of HPV infection with a national HPV immunization programme for pre-adolescent girls would prevent the majority of CC related deaths and associated costs.