Background Nicotine and alcohol co-abuse is highly prevalent. Recently, we have shown that nicotine infusion in the basal forebrain (BF) increases alcohol consumption. Since nucleus accumbens (NAc) is the terminal brain region associated with drug addiction, we hypothesize that nicotine infusion in the BF may enhance alcohol induced activation of NAc. Methods Adult male Sprague-Dawley rats were surgically implanted with bilateral guide cannulas in the BF. Following post-operative recovery, rats were divided into four groups: 1) ACSF+W group received artificial cerebrospinal fluid (ACSF; 500 nl/side) in the BF and systemic water [intragastric (ig); 10 ml/kg; N=5], 2) EtOH group received ACSF in the BF (500 nL/side) and systemic alcohol (ig; 3 g/Kg; N=5), 3) NiC group received nicotine in the BF (75 pmole/500nl/side) and systemic water (ig; 10 mL/Kg; N=5) and 4) NiC+EtOH group received nicotine in the BF (75 pmole/500nl/side) and systemic alcohol (ig; 3 g/Kg; N=5). Rats were euthanized two hours after treatment to examine c-Fos expression in the NAc by immunohistochemistry. Results All injections sites were localized in the BF. Two way ANOVA (ig vs infusion) revealed significant main effects of both treatments (ig and infusion, p < 0.001) on c-Fos expression in the NAc shell but not in the core. Subsequent post-hoc test (Bonferroni’s) revealed that as compared to ACSF+W group, c-Fos expression was significantly increased in the shell of NAc of rats in all three (EtOH, NiC and NiC+EtOH) groups with maximal increase observed in NiC+EtOH group. Conclusions The results suggests: 1) BF nicotine infusion induced c-Fos in both core and the shell region of NAc at levels comparable to those observed after systemic alcohol administration; 2) BF nicotine infusion with systemic alcohol induced a significant additive increase in c-Fos expression only in the NAc shell region. These findings implicate the BF in alcohol and nicotine co-use.