The c-fos immediate-early gene is induced by morphine and other drugs of abuse in the nucleus accumbens (NAc), a mesolimbic region implicated in drug abuse and reward. This study examined the role of c-fos in the acquisition and expression of the conditioned place paradigm (CPP) in the rat by suppressing Fos protein expression with c-fos antisense oligodeoxynucleotides (ODNs). CPP was completely prevented by c-fos antisense ODN infused bilaterally into the NAc prior to each systemic morphine injection, whereas sense and missense NAc injections had no effect on CPP. NAc administration of c-fos antisense ODN after the last systemic morphine conditioning session did not affect the expression of morphine-CPP. These results suggest that c-fos expression in NAc is necessary for the acquisition but not expression of morphine-CPP, and they have important implications for understanding conditioned behaviours and drug craving and addiction.