To assess the role of dopamine metabolism-related genes in the genetic liability to chronic headache with drug abuse (DA). We performed a genetic association study using four functional polymorphisms of the dopamine receptor 4 (DRD4), dopamine transporter (DAT), mono-amino-oxidase A (MAOA) and cathecol-O-methyl-transferase (COMT) genes in 103 patients with chronic daily headache associated with DA (CDHDA). Control samples were 117 individuals without headache or DA (controls) and 101 patients with episodic migraine without aura and without DA (MO). No differences were found at the COMT and MAOA genes among the three groups investigated. Allele 4 of DRD4 was significantly overrepresented in patients with MO compared with both controls and CDHDA. Allele 10 of the DAT gene was significantly underrepresented in patients with CDHDA when compared with the MO group. Genetic variability at the DRD4 gene is involved in the predisposition to episodic MO but not to DA, while liability to CDHDA may involve genetic variability at the DAT gene in comparison with episodic MO.