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Q-switched alexandrite lasers (QSALs) have been used for the treatment of acquired bilateral nevus of Ota–like macules (ABNOMs). Currently, picosecond alexandrite laser (PSAL) pulses have become available for pigmentary disorders. However, no studies have compared PSAL and QSAL in the treatment of ABNOM.We sought to compare the efficacy and safety of PSAL and QSAL in the treatment of ABNOM.Each patient (n = 30) received 3 treatments at 6-month intervals. Matching areas were delimitated on the face of each patient (left/right comparison); 1 side was treated with PSAL and the other side was treated with QSAL. The safety and efficacy of the 2 lasers were determined by visual assessment and self-report from patients 6 months after the final treatment.The PSAL-treated area achieved significantly better clearance (3.73 vs 2.4) with less severe pain (4.47 vs 5.16). The incidence rate of postinflammatory hyperpigmentation was 27.77% and 54.44% for the PSAL and QSAL treatments, respectively, and the duration of postinflammatory hyperpigmentation was 1.32 and 1.74 months, respectively (P < .001).The limitations of our study include the small sample size and the lack of objective evaluation.Compared with QSAL, PSAL therapy afforded significantly better clinical outcomes and fewer side effects in the treatment of ABNOM.