This study explored whether functional genetic variants previously associated with nicotine dependence are associated with regional cerebral blood flow (rCBF) changes during nicotine abstinence (compared to satiety; smoking as usual). Thirteen smokers participating in a prior arterial spin labeled (ASL) perfusion MRI study were scanned on two occasions (after >12h abstinence vs. satiety), and were genotyped for variants in the dopamine D2 receptor (DRD2-141 Ins/DelC; DRD2 C957T); a dopamine metabolizing enzyme (COMT val(158) met), and the mu opioid receptor (OPRM1 A118G). Significantly greater CBF increases were found in regions previously linked with cigarette cravings among carriers of the DelC variant of DRD2-141 and among the COMT val/val group. Smokers with TT genotypes for the DRD2 C957T exhibited less change in rCBF in abstinence relative to satiety, compared to those with CC or CT genotypes. Finally, smokers with OPRM1 AA genotypes showed significant increases in CBF in regions associated previously with cigarette cravings. While preliminary, these results suggest a neural mechanism through which these genetic variants may be linked with nicotine dependence, and provide further support for increased biological vulnerability in these subgroups of smokers.