Background The treatment of acne scars with fractional CO2 lasers is gaining increasing impact, but has so far not been compared side-by-side to untreated control skin. Objective In a randomized controlled study to examine efficacy and adverse effects of fractional CO2 laser resurfacing for atrophic acne scars compared to no treatment. Methods Patients (n?=?13) with atrophic acne scars in two intra-individual areas of similar sizes and appearances were randomized to (i) three monthly fractional CO2 laser treatments (MedArt 610; 1214?W, 4856?mJ/pulse, 13% density) and (ii) no treatment. Blinded on-site evaluations were performed by three physicians on 10-point scales. Endpoints were change in scar texture and atrophy, adverse effects, and patient satisfaction. Results Preoperatively, acne scars appeared with moderate to severe uneven texture (6.15 +/- 1.23) and atrophy (5.72 +/- 1.45) in both interventional and non-interventional control sites, P?=?1. Postoperatively, lower scores of scar texture and atrophy were obtained at 1 month (scar texture 4.31 +/- 1.33, P?<?0.0001; atrophy 4.08 +/- 1.38, P?<?0.0001), at 3 months (scar texture 4.26 +/- 1.97, P?<?0.0001; atrophy 3.97 +/- 2.08, P?<?0.0001), and at 6 months (scar texture 3.89 +/- 1.7, P?<?0.0001; atrophy 3.56?+/- 1.76, P?<?0.0001). Patients were satisfied with treatments and evaluated scar texture to be mild or moderately improved. Adverse effects were minor. Conclusions In this single-blinded randomized controlled trial we demonstrated that moderate to severe atrophic acne scars can be safely improved by ablative fractional CO2 laser resurfacing. The use of higher energy levels might have improved the results and possibly also induced significant adverse effects. Lasers Surg. Med. 44: 447452, 2012. (C) Wiley Periodicals, Inc.