The objective was to assess the efficacy of the lidocaine 2. 5%/prilocaine 2.5% combination cream during CO2 laser vaporisation treatment of human papillomavirus-related anogenital lesions. The cream was applied 1 to 30 min beforehand. Patients assessed pain using a visual analogue scale. Regardless of the site and lesion surface area, anaesthesia was greatest when the cream was applied 5 to 15 min before treatment. Extra-cervical lesions (vagina, vulva, perineum, anus) were globally less painful than cervical lesions. Lesion surface area is a decisive factor in pre-operative anaesthesia. Small surface-area lesions (< 1 cm2) had significantly greater anaesthesia than larger surface area-lesions (> 5 cm2) (p<0.00001). The study cream proved particularly useful for complete anaesthesia in ambulatory treatment of anal (70%) and urethral (60%) mucosa lesions compared to the uterine cervix (p = 0.03). In terms of anaesthetic efficacy and cost-related benefits, the lidocaine/prilocaine cream is an effective and interesting alternative to locoregional intra-lesional anaesthesia or even to general anaesthesia, for excision and destruction of human papillomavirus-related anogenital lesions.