BACKGROUND: Actinic cheilitis (AC) may progress into fully developed squamous cell carcinoma with a relatively high risk of metastasizing and therefore requires early identification and treatment.OBJECTIVES: To assess the clinical and histological long-term outcome as well as the safety and tolerability of sequential use of photodynamic therapy (PDT) and imiquimod in AC.METHODS: Patients with histologically confirmed grade 1 and 2 AC received two methyl aminolaevulinate-PDT sessions 2weeks apart. After a 2-week rest period the patients started applying imiquimod 5% cream 3days per week for 4weeks. At the first follow-up visits at 3 and 6months, noncomplete clinical responders were biopsied and excluded from the study if histological alterations were indicative for AC. At the last 12-month follow-up all remaining patients were biopsied. Adverse events were noted at weeks 2, 4, 6 and 8 of the treatment phase and at every visit of the follow-up period.RESULTS: Of the 34 enrolled patients, 30 completed the study. Complete clinical response was achieved by 27 patients in 3months. At 6months, clinical and histological recurrence occurred in two patients, while at 12months the complete clinical cure rate obtained was 80% and the histological complete cure rate was 73%. Treatment was well tolerated and adverse events were as expected and transient.CONCLUSION: Sequential use of PDT and imiquimod cream is of significant benefit for the treatment of AC. Further studies are needed in order to confirm the improved outcome using the combination treatment, to clarify the involved mechanisms and to optimize the therapeutic protocol.