Previous research has demonstrated that concurrent systemic administration of CB(1) cannabinoid and mu-opioid receptor agonists increases feeding in rats. However, the possible neural loci of this cooperative effect have yet to be identified. These studies tested whether the nucleus accumbens shell may be one site of the interactive effects of opioid and cannabinoid ligands on feeding. Injection of the mu-opioid agonist DAMGO (at 0, 0.025, 0.25, or 2.5 µg/0.5 µl/side) directly into the rat nucleus accumbens shell increased feeding on a sweetened-fat diet, and this effect was blocked by pretreatment with either the mu-opioid antagonist naltrexone (20 µg/0.5 µl/side) or the CB(1) antagonist SR141716 (0.5 µg/0.5 µl/side). Activation of nucleus accumbens shell CB(1) receptors with WIN55212-2 alone (at 0.1 or 0.5 µg/0.5 µl/side) had no apparent effect on food intake. However, local injections of the low dose of DAMGO (.025 µg/0.5 µl/side) in this region along with WIN55212-2 (at 0.25 or 0.50 µg/0.5 µl/side) increased feeding above that induced by DAMGO alone. These data suggest an important modulatory role for cannabinoid receptors in the expression of feeding behaviors in response to mu-opioid receptor activation of the nucleus accumbens shell.