The objective of this study was to investigate the association between polymorphisms of the hypocretin receptor 2 gene (HCRTR2) and the risk of cluster headache (CH). The study is a meta-analysis of published case-control studies investigating the association between polymorphisms of the HCRTR2 gene and CH. Pooled odds ratios (OR) were estimated using both random (RE) and fixed effects (FE) models. Three studies, performed in five different European countries, with 593 cases and 599 controls, were included in the study. Allele G of the G1246A HCRTR2 polymorphism was significantly associated with CH (FE OR 1.58, CI 95% 1.27-1.95; RE OR 1.55 (1.14-2.12)). Carriers of the GG genotype showed a higher disease risk compared to the remaining genotypes (FE OR 1.75, CI 95% 1.37-2.25; RE OR 1.69, CI 95% 1.11-2.58). Our data confirm that the G1246A polymorphism of the HCRTR2 gene may modulate the genetic risk for CH.