Individual and strain variability in the effects of nicotine suggests the involvement of a genetic component in nicotinic cholinergic receptor (nAChR) function, which may help explain nicotine's variable behavioral and pharmacological effects in different individuals. The present study evaluated differential responses to the discriminative stimulus (DS) and rewarding properties of nicotine in Lewis (LEW) and Fischer-344 (F-344) rats. Drug discrimination (DD) data suggest that the LEW rat is more sensitive to nicotine as LEW rats acquired the nicotine discrimination at a dose of 0.4 mg/kg, whereas F-344 rats acquired the dose of 0.9 mg/kg (all nicotine doses expressed as free base). Similarly, LEW rats exhibited nicotine-conditioned place preference (CPP) at 0.6 mg/kg, whereas the F-344 rats did not. Subsequent testing with a higher dose (0.9 mg/kg) failed to maintain the nicotine-CPP in the LEW rats. Conversely, nicotine-place preference in the F-344 rats was not changed at the higher dose. Taken together, these results suggest potential differences of sensitivities in LEW and F-344 rats to the rewarding and discriminative stimulus (DS) properties of nicotine. These findings support previous research by demonstrating that the F-344 rat is less sensitive to nicotine compared to the LEW rat.