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Actinic cheilitis (AC) is a common precancerous condition for which a safe, effective, rapid, and cosmetically favorable treatment is needed. The objective of this study was to assess the safety and efficacy of the long-pulsed pulsed dye laser (LP PDL) (595 nm) with photodynamic therapy (PDT) for the treatment of AC. This study was designed to be a prospective, proof-of concept pilot study to assess safety and efficacy of LP PDL in conjunction with topical 20% 5-aminolevulinic acid solution PDT for the treatment of AC. Control patients received LP PDL alone. The setting was an outpatient clinical research center. A volunteer sample of 21 patients with biopsy-proven AC was enrolled (age range, 42-86 years; skin types I-III). All patients were refractory to prior therapies. Patients with a history of herpes labialis were pre-treated with famcyclovir. Nineteen patients received one-to-three treatments of topical 20% 5-aminolevulinic acid for 2-3 hours, followed by LP PDL (595 nm) at monthly intervals. Two control patients received one treatment with LP PDL alone. Patients in the ALA-LP PDL group were followed at 1, 2, 3, 6, 9, and 12 months. Clearance of AC was assessed by clinical evaluation. Control patients were followed to the one month interval. We observed none-to-mild pain; slight-to-moderate erythema; no crusting, purpura, or scarring; treatment time of less than one minute; and complete resolution of post-operative erythema by day three. Complete clearance was achieved in 13/19 (68%) of patients following a mean of 1.8 treatments (7/13 (37%) after one, 2/13 (11%) after two, and 1/13 (21%) after three treatments). Patients were followed for a mean of 4.1 (range 1-12) months. Among the remaining cases, partial clearing was achieved in two patients, recurrence during the follow-up interval was observed in one patient, and failure to follow-up occurred in three patients. Post-operative impetiginization occurred in three patients with erosive AC, which resolved with dicloxacillin therapy. Among the control patients, no clearing was observed. Treatment of AC using LP PDL (595 nm) at nonpurpuric parameters following topical application of 5-aminolevulinic acid at short incubation times is safe and effective. It may offer the advantages of rapid incubation, treatment, and recovery times, minimal discomfort, excellent cosmetic outcome, and good efficacy rates. Patients with erosive AC should receive antibacterial prophylaxis. Multiple treatments may be required for complete clearing.