Pleiotrophin (PTN) and midkine (MK) are growth factors that modulate alcohol consumption and reward. Since both PTN and MK limit the rewarding effects of alcohol, pharmacological potentiation of the PTN and MK signaling pathways has been proposed for the treatment of alcohol use disorders (AUD). Although the use of this therapy in the prevention of alcohol relapse is important, the potential role of these cytokines in extinguishing alcohol-induced seeking behavior is a key question that remains unanswered. To fill this gap, we have now studied the extinction of the conditioned place preference (CPP) induced by different doses of alcohol in Ptn knockout (Ptn-/-) and Mk knockout (Mk-/-) mice. The data confirm a higher sensitivity of Ptn-/- mice to the conditioning effects of a low dose (1 g/kg) and a rewarding dose (2 g/kg) of alcohol, while Mk-/- mice are only more susceptible to the conditioning effects of the low dose of this drug. More importantly, the percentage of Mk-/- mice, not Ptn-/- mice, that efficiently extinguished alcohol-induced CPP was significantly higher than that of Wt mice. Taken together, the data presented here confirm that Ptn and Mk are genetic factors that determine the conditioning effects of alcohol in mice and that Mk is a novel factor that plays an important role in the extinction of alcohol-induced CPP.