Cluster headache is a disorder with increased hereditary risk. Associations between cluster headache and polymorphism rs2653349 of the HCRTR2 gene have been demonstrated. The less common allele (A) seems to reduce disease susceptibility. The polymorphism rs5443 of the GNB3 gene positively influences triptan treatment response. Carriers of the mutated T allele are more likely to respond positively compared to C:C homozygotes, when treated with triptans. DNA was extracted from buccal swabs obtained from 636 non-related Southeastern European Caucasian individuals and was analyzed by real-time PCR. Gene distribution for the rs2653349 was G:G = 79.1%, G:A = 19.2%, and A:A = 1.7%. The frequency of the wild-type G allele was 88.7%. The frequencies for rs5443 were C:C = 44.0%, C:T = 42.6%, and T:T = 13.4%. The frequency of the wild-type C allele was 65.3%. The frequency distribution of rs2653349 in the Southeastern European Caucasian population differs significantly when compared with other European and East Asian populations, and the frequency distribution of rs5443 showed a statistically significant difference between Southeastern European Caucasian and African, South Asian, and East Asian populations. For rs2653349, a marginal statistically significant difference between genders was found (p = 0.080) for A:A versus G:G and G:A genotypes (OR = 2.78), indicating a higher representation of male homozygotes for the protective mutant A:A allele than female. No statistically significant difference was observed between genders for rs5443. Cluster headache pathophysiology and pharmacotherapy response may be affected by genetic factors, indicating the significant role of genotyping in the overall treatment effectiveness of cluster headaches.