Background: Laser treatment of acne scars is common, but quality evidence on its efficacy is still needed.Our study aimed to compare picosecond laser and non-ablative fractional laser's efficacy and safety in treating acne atrophic scars.Methods: This was a randomized, split-face double-blind trial recruiting patients with acne atrophic scars. Facial halves were randomly divided and treated with fractionated frequency-doubled 1,064/532 nm picosecond Nd:YAG laser or non-ablative fractional 1,540 nm Er: glass laser. ECCA score (echelle d'evaluation clinique des cicatrices d'acne) and skin flatness measured with a non-invasive phaseshift rapid in vivo measurement of skin (PRIMOS) system were evaluated one month after the last treatment.Results: Twenty-two Fitzpatrick skin type IV patients were included in this study, with an average age of 29.68 years, an average duration of acne scars of 8.8 years. Picosecond laser impacted all acne scar types (before and after treatment; P=0.000 for all types, P<0.001 for V-type, P=0.002 for U-type, and P=0.021 for M-type) and more pronounced effect on ECCA score than non-ablative laser for V-type and U-type acne scars. After treatment, each treatment site's height was significantly lower than that before treatment (P=0.041) in the picosecond group but not in the non-ablative group (P=0.785). The reported erythema rate was higher in patients treated with a picosecond laser, while edema, exudation, purpura, pain, and long-term AEs were similar between the groups.Conclusions: Fractionated frequency-doubled 1,064/532 nm Picosecond Nd: YAG laser showed better efficacy in treating acne atrophic scars than the alternative and provided satisfactory safety with added improvement in pores and the glossiness of the skin.Registration number: ChiCTR2100045982 (comparison of fractionated frequency-doubled 1,064/532 nm picosecond Nd: YAG lasers and nonablative fractional 1,540 nm Er: glass in the treatment of facial atrophic scar: a randomized, split-face, double-blind controlled trial).