OBJECTIVES: The aim of the present study was to analyze the effect of an enhanced systematic dose of nicotine on osseointegration of titanium implants. MATERIAL AND METHODS: Sixteen female rabbits received either nicotine (n=8) or saline (n=8) administered subcutaneously via mini-osmotic pumps for 2 months. The pump delivered 6 mug/kg/min of nicotine for the animals in the test group. Blood was withdrawn and plasma cotinine levels were measured weekly. Thirty-two titanium implants were inserted into the femur and tibia of all rabbits after 4 weeks and after 6 weeks of nicotine/placebo exposure. Thus, 2- and 4-week healing groups were created. Biomechanical evaluation by (i) resonance frequency analysis test (RFA) on all implants after insertion and before sacrifice and (ii) removal torque test (RMT) on tibial implants before sacrifice was performed. All implants placed in the femur were processed to undecalcified ground sections. The percentage of bone-to-implant contact (BIC) and of bone area within the threads (BD-i) were measured. RESULTS: No significant difference in RMT and RFA values was found between the test and the control group. Histomorphometric measurements of the BIC and the peri-implant BD-i showed no significant differences between the test and the control group after 2 or after 4 weeks. CONCLUSION: Nicotine exposure for a short period of time even in a high dose did not have a significant impact on implant osseointegration in rabbits.