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Objectives: Quality-switched (QS) lasers are known to be an effective treatment for removing solar lentigines, however, high incidence of post-inflammatory hyperpigmentation (PIH) is a concern in darker skin types. The objective of this study was to evaluate the efficacy and safety of a dual-wavelength and dual-pulse width picosecond Nd:YAG laser for removing solar lentigines in Asians., Methods: This was a prospective, IRB-approved study. Twenty cases with solar lentigines on the face were enrolled for treatment and evaluated at 1- and 3-month after the final treatment. Results were assessed by blinded evaluators using a 5-grade percentage improvement scale and Melanin index (MI) measured by a reflectance spectrophotometer. A patient self-assessment questionnaire was also administered using a 5-grade improvement scale. Additional treatment was performed if the improvement was less than 75% or the lentigo partially remained after 4 weeks. Histological evaluation was performed to compare the differences between the current picosecond laser and a QS Nd:YAG laser 532-nm using light and electron microscopy., Results: Forty-three lesions in 20 females, skin type III or IV, age 53.7 ± 9.75 were treated and evaluated. The laser setting was: 532-nm, 750 picoseconds, average fluence of 0.35 ± 0.06 J/cm [2] using a spot size of 3 or 4 mm. Forty lesions (93.02%) achieved over 75% clearance with a single treatment and the other three lesions (6.98%) needed two treatments. PIH occurred only in 4.65% of lesions. The average score of the blinded evaluators' assessment was 4.77 and 4.58 on a 5-grade percentage improvement scale. The patients' self-assessment rating was 4.76 and 4.67 on a 5-grade scale at 1- and 3-month follow-up, respectively. The improvement rate of relative MI (MI in the lesion minus that of the normal area) was 77.60 ± 36.27% and 76.93 ± 20.95% at 1-and 3-month follow-up. Histology showed vacuolar formation by both lasers in the epidermis that were different sizes between lasers. Electron microscopy showed destruction of melanosomes with surrounding tissue damage with the QS laser and without particular damage with the picosecond laser., Conclusions: To the best of our knowledge, this is the first study using a picosecond Nd:YAG laser 532-nm for removing solar lentigines in darker skin types that includes histological evaluation. Although there are many options to treat solar lentigines, our results suggest that picosecond laser with preferable endpoint determination can be a safer and more effective treatment over conventional treatments in Asian patients. Lasers Surg. Med. 50:851-858, 2018. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)