BACKGROUND: Topical local analgesic and anaesthetic agents have been used both pre- and immediately post-harvest on split-thickness skin graft (STSG) donor site wounds (DSW). There is no systematic review of their effectiveness in providing post-harvest analgesia, or of the possible toxic effects of systemic absorption. This study is designed to address the question of which agent, if any, is favoured over the others and whether there are any safety data regarding their use. METHODS: Systematic literature review of randomised controlled trials of topical agents applied to STSG DSWs, with a view to providing analgesia. Studies identified via search of Cochrane and EBSCO databases. No restrictions on language or publication year. Primary outcomes: pain at the time of (awake) STSG, and post-harvest pain (up to first dressing change). Secondary outcome was serum medication levels relative to published data on toxic doses. Cochrane risk of bias assessment tool utilised in assessment of included studies. At least 2 reviewers screened and reviewed included studies. A narrative review is presented. RESULTS: There were 11 studies meeting inclusion criteria. Overall methodological quality and patient numbers were low. Topical eutectic mixture of lidocaine and prilocaine pre-harvest affords good local anaesthesia in awake STSG harvesting. Topical bupivacaine (5 studies) or lidocaine (1 study) gave significantly better post-harvest anaesthesia/analgesia than placebo. Topical morphine performs no better than placebo. Topical local anaesthetic agents at reported doses were all well below toxic serum levels. CONCLUSIONS: Topical local anaesthetics (lidocaine or bupivacaine) provide good analgesia, both during and after STSG harvest, at well below toxic serum levels, but there are no good data determining the best local anaesthetic agent to use. There is no evidence morphine performs better than placebo.