In the 1990s, 5-flourouracil (5-FU) was introduced as a treatment for keloids; however, there is still no consensus on its use. In order to guide clinical practice, a systematic review of the clinical evidence on the effectiveness of 5-FU in keloid treatment was carried out. Eight databases were searched on 10 September 2014 using the terms "keloid" and "5-FU", together with all synonyms of these terms. Two reviewers selected original research reports using 5-FU alone or combined with a maximum of 2 other therapies. Eighteen papers were found that reported either on intralesional 5-FU alone, or on 5-FU combined with triamcinolone acetonide (TAC:5-FU) or excision, including 482 patients. 5-FU treatment was effective in 45-96% of patients, but only TAC:5-FU may perform better than TAC alone. Due to a poor level of evidence, further research should establish the superiority of repeated intralesional TAC:5-FU injections over TAC alone with several doses and injection schedules.