Review articles have focused attention on and cited possible reasons for the nonreplication of genetic association studies. Herein, we illustrate how one might work through these possible reasons to make a judgment about the most plausible reason(s) when faced with two or more studies which yield seemingly inconsistent results. In the first study, 342 treatment-seeking smokers were genotyped for the Val108Met polymorphism in the functional catechol-O-methyltransferase (COMT) locus. Alleles coding Val at codon 108 are denoted as H and those coding Met are denoted as L. An association between presence of the "H" (high activity) allele and pretreatment level of nicotine dependence level using the Fagerstrom Test for Nicotine Dependence was detected (P = 0.0072), after controlling for baseline body mass index (BMI, kg/m2), depression symptoms, and age. To validate this initial finding, 443 treatment-seeking smokers from an independent smoking cessation clinical trial were genotyped for the COMT polymorphism. Within the second study, no association between presence of the "H" allele and nicotine dependence was detected (P = 0.6418) after controlling for baseline BMI, depression symptoms, and age. We critically reviewed both studies with regard to often cited reasons for nonreplication, including type I error, population stratification, low statistical power, and imprecise measures of phenotype. Although in our opinion the failure to replicate the initial association in the second study is likely either the result of low statistical power to detect a small effect or effect heterogeneity, thorough analyses failed to definitively identify the reason for nonreplication. Copyright © 2005 American Association for Cancer Research.