Pharmacological and neuroanatomical evidence suggest the involvement of the dopaminergic system in obsessive-compulsive disorder (OCD). Analysis of the 48-bp dopamine receptor D(4) (DRD4) gene polymorphism in a sample of 210 OCD patients and 202 healthy control subjects showed a significant association (chi(2)=27.5, df=6, p=0.0003). This difference was attributable to a lower frequency of allele 4R in OCD patients compared with the control group (chi(2)=9.33, p=0.0027). However, we did not replicate previous findings of an association between the 7R allele and OCD patients with tics. Finally, we analyzed a sub-sample of 86 OCD families. E-TDT analysis in 70 informative parents did not confirm the association observed in our case-control analysis. In conclusion, the current study cannot exclude an association between DRD4 gene and OCD in the largest sample analyzed. However, further studies will be required to confirm if the DRD4 gene is involved in the pathogenesis of this disorder.