The use of pulsed dye laser (PDL) and fractional CO2 (FX CO2 ) laser therapy to treat and/or prevent scarring following burn injury is becoming more widespread with a number of studies reporting reduction in scar erythema and pruritus following treatment with lasers. While the majority of studies report positive outcomes following PDL or FX CO2 therapy, a number of studies have reported no benefit or worsening of the scar following treatment. The objective of this study was to directly compare the efficacy of PDL, FX CO2 , and PDL + FX CO2 laser therapy in reducing scarring post burn injury and autografting in a standardized animal model. Eight female red Duroc pigs (FRDP) received 4 standardized, 1 in. x 1 in. third degree burns that were excised and autografted. Wound sites were treated with PDL, FX CO2 , or both at 4, 8, and 12 weeks post grafting. Grafts receiving no laser therapy served as controls. Scar appearance, morphology, size, and erythema were assessed and punch biopsies collected at weeks 4, 8, 12, and 16. At week 16, additional tissue was collected for biomechanical analyses and markers for inflammatory cytokines, extracellular matrix (ECM) proteins, re-epithelialization, pigmentation, and angiogenesis were quantified at all time points using qRT-PCR. Treatment with PDL, FX CO2 , or PDL + FX CO2 resulted in significantly less contraction versus skin graft only controls with no statistically significant difference among laser therapy groups. Scars treated with both PDL and FX CO2 were visually more erythematous than other groups with a significant increase in redness between two and three standard deviations above normal skin redness. Scars treated with FX CO2 were visually smoother and contained significantly fewer wrinkles. In addition, hyperpigmentation was significantly reduced in scars treated with FX CO2 . The use of fractional carbon dioxide or pulsed dye laser therapy within 1 month of autografting significantly reduced scar contraction versus control, though no statistically significant difference was detected between laser modalities or use of both modalities. Overall, FX CO2 therapy appears to be modestly more effective at reducing erythema, and improving scar texture and biomechanics. The current data adds to prior studies supporting the role of laser therapy in the treatment of burn scars and indicates more study is needed to optimize delivery protocols for maximum efficacy. Lasers Surg. Med. 50:78-87, 2018. © 2017 Wiley Periodicals, Inc.