Behavioural and pharmacological effects of Delta9-tetrahydrocannabinol (THC) and nicotine are well known. However, the possible interactions between these two drugs of abuse remain unclear in spite of the current association of cannabis and tobacco in humans. The present study was designed to analyse the consequences of nicotine administration on THC-induced acute behavioural and biochemical responses, tolerance and physical dependence. Nicotine strongly facilitated hypothermia, antinociception and hypolocomotion induced by the acute administration of THC. Furthermore, the co-administration of sub-threshold doses of THC and nicotine produced an anxiolytic-like response in the light - dark box and in the open-field test as well as a significant conditioned place preference. Animals co-treated with nicotine and THC displayed an attenuation in THC tolerance and an enhancement in the somatic expression of cannabinoid antagonist-precipitated THC withdrawal. THC and nicotine administration induced c-Fos expression in several brain structures. Co-administration of both compounds enhanced c-Fos expression in the shell of the nucleus accumbens, central and basolateral nucleus of the amygdala, dorso-lateral bed nucleus of the stria terminalis, cingular and piriform cortex, and paraventricular nucleus of the hypothalamus. These results clearly demonstrate the existence of a functional interaction between THC and nicotine. The facilitation of THC-induced acute pharmacological and biochemical responses, tolerance and physical dependence by nicotine could play an important role in the development of addictive processes.