Q-switched ruby laser is known as an effective treatment for removing solar lentigines. However, high incidence of post-inflammatory hyperpigmentation is a concern in Asian skin. Picosecond Nd:YAG lasers have the advantage of destroying melanosomes through photoacoustic effects. The objective of this study was to compare the efficacy and safety of picosecond 532 nm Nd:YAG laser with Q-switched ruby laser for removing facial solar lentigines. In this study, cases with solar lentigines on the face were enrolled for the left-right spilt-face treatment comparison. The patients were examined by in vivo harmonic generation microscopy at baseline, 3 weeks and 6 weeks after laser treatment. Our results suggested that picosecond 532 nm Nd:YAG laser provided a treatment as effective as ruby laser for facial solar lentigines. Nevertheless, picosecond 532 nm Nd:YAG laser caused less treatment-associated pain and a relatively less incidence of post-laser hyperpigmentation, comparing to ruby laser.