The brain synaptic vesicular amine transporter SLCA18A2 is a key component for the uptake of monoamines like dopamine or serotonin into vesicles. We have analyzed seven DNA polymorphisms located in the genomic region of SLC18A2 for association with alcohol- and nicotine dependence, using a family-based design. Our sample comprised 131 families with alcohol- dependent offspring and 96 families with at least one nicotine-dependent offspring. For the alcohol- dependent sample, we found statistical significant association for two single markers (rs363387, P = 0.03; rs363333, P = 0.0066) as well as for several haplotypes ( minimal P = 0.0038). When the sample with alcohol dependence was stratified according to gender, we observed increased association for the male subgroup ( rs363387, P = 0.0011). None of the markers showed association in the sample of families with nicotine dependence. However, analysis of a combined sample of alcohol and nicotine-dependent families resulted in single markers as well as several haplotypes showing statistical significant association with substance dependence ( minimal P = 0.0044). We conclude that DNA polymorphisms located in SLC18A2 might contribute to the development of substance dependence.