Background Laser pulses with nanosecond duration (NSL) have been the golden standard to destroy the pigment particles in skin. It is still controversially discussed whether picosecond pulses (PSL) are superior for tattoo removal. Objectives To compare the efficacy and the adverse reactions of nanosecond and picosecond laser pulses in a comparative study. Methods The prospective study included 23 subjects with 30 black or coloured tattoos, which were split into two halves treated with either a new PSL (532, 1064 nm) or standard NSL (694 nm). The lasers were applied at regular time intervals of 4 weeks for up to eight treatments. Tattoo clearance (primary endpoint), pain and adverse reactions (secondary endpoints) were appraised by physicians, blinded observers, and by subjects. The extent and duration of adverse reactions were additionally assessed by using a questionnaire and photo-documentation after each treatment session. Results The tattoo clearance appeared to be more effective for PSL compared to NSL but without statistical significance (P > 0.05). Pretreated tattoos responded better to laser treatments than previously untreated tattoos. Subjects felt significantly less pain with PSL than with NSL (P < 0.001). Transient adverse reactions were statistically less pronounced lasting shorter for PSL as for NSL, especially blistering, pruritus, and burning sensation. Hypopigmentation appeared after NSL treatments only, whereas hyperpigmentation was caused by both lasers. No scarring was detected with either laser. Conclusions Both laser systems enable acceptable clearance of most tattoos in the present study. PSL cause less collateral skin damage as compared to NSL.