Background: Theory predicts that picosecond lasers should be more effective than the currently available nanosecond lasers in removing tattoo ink. In addition to thermal confinement, such pulse widths cause optimal photomechanical disruption of the target. Objective: This study compared the efficacy of the picosecond titanium:sapphire (795 nm, 500 psec) laser and the Q-switched alexandrite (752 nm, 50 nsec) laser in the treatment of tattooed guinea pigs. Methods: Six albino guinea pigs, each with 6 uniformly 1 cm circular black tattoos, were treated. Three of the tattoos were divided into 2; one half was treated with the titanium:sapphire laser and the other half with the alexandrite laser. Fluences used for both lasers were 6.11, 4.24, and 2.39 J/cm² with spot sizes of 1.25, 1.5, and 2 mm, respectively. The remaining spots served as control. Clinical evaluation and biopsies were performed at baseline and at 11 and 16 weeks after a single laser treatment. Results: Greater clearance of tattoo was observed in titanium:sapphire laser–treated areas in 2 of the 4 surviving guinea pigs. In some areas total clearing was observed after the single titanium:sapphire laser treatment. Clearing improved with higher fluences. No scarring was present. Histologic results showed similar findings. Conclusion: Our findings suggest that the picosecond titanium:sapphire laser is more effective than the Q-switched alexandrite laser in removing tattoo pigment and may be of significant clinical utility. (J Am Acad Dermatol 1999;40:603-6.)