Although epidemiological studies reveal that cigarette smoking is inversely associated with Alzheimer's disease (AD) and Parkinson's disease (PD), the underlying mechanism remains largely unknown. Considering the facts that amyloid precursor protein-binding protein, family B, member 1 (APBB1) is mapped to a suggestive linkage region on chromosome 11 for nicotine dependence (ND), and has been implicated in the pathogenesis of AD and PD, it represents a plausible candidate for genetic study of ND. Five single nucleotide polymorphisms (SNPs) within APBB1 were genotyped in a sample consisting of 2,037 participants of either African-American (AA) or European-American (EA) origin, and examined their associations with ND assessed by three commonly used measures: Smoking Quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerström Test for ND (FTND). Individual SNP-based association analysis showed that all five SNPs are associated with at least one ND measure in one of the three samples; however, only the association of SNP rs4758416 with SQ and HSI remained significant after correction for multiple testing in the pooled sample. Haplotype analysis demonstrated three major haplotypes significantly associated with ND after Bonferroni correction. Formed by rs4758416-rs10839562-rs1079199, haplotype C-C-T showed positive association with FTND in the AA and pooled samples, and conversely, haplotype G-C-T showed negative association with SQ and HSI in AA and EA samples. Another haplotype, C-T-G, formed by rs10839562-rs1079199-rs8164, was significantly associated with HSI in the EA sample. Based on these findings, we conclude that APBB1 represents an important candidate gene in the genetic study on ND and neurodegenerative diseases and warrants further investigation in future.