Background: Pulsed dye laser is the gold standard for treatment of port-wine stain birthmarks but multiple treatments are required and complete resolution is often not achieved. Posttreatment vessel recurrence is thought to be a factor that limits efficacy of PDL treatment of PWS. Imiquimod 5% cream is an immunomodulator with antiangiogenic effects. Objective: We sought to determine if application of imiquimod 5% cream after PDL improves treatment outcome. Methods: Healthy individuals with PWS were treated with PDL and then randomized to (...) apply posttreatment placebo or imiquimod 5% cream for 8 weeks. Chromameter measurements for 57 PWS sites were taken at baseline and compared with measurements taken 8 weeks posttreatment. The Δa and ΔE were measured to quantify treatment outcome. Results: Two patients developed minor skin irritation. Other adverse effects were not noted. Average a was 0.43 for PDL + placebo sites and 1.27 for PDL + imiquimod sites indicating a greater reduction in erythema with imiquimod. Average E was 2.59 for PDL + placebo and 4.08 for PDL + imiquimod, again indicating a greater color improvement with imiquimod. Limitations: Effects were evaluated after a single treatment and duration of effect is unknown. Conclusion: Combined selective photothermolysis and antiangiogenic therapy may enhance PWS treatment efficacy. © 2011 by the American Academy of Dermatology, Inc. (shrink)