Primary headaches are common neurological problem in the world. Migraine (M) and tension type headache (TTH) are the leaders in the structure of primary headaches in the population; (1) Background: The study of the association of single nucleotide variants (SNVs) of MTHFR (meth-ylenetetrahydrofolate reductase) and HTR2C (5-Hydroxytryptamine Receptor 2C) genes with M and TTH development in the European population in Siberia (Russia); (2) Methods: 192 adults were examined: 82 (42.7%) males and 110 (57.3%) females. Control group: 81 healthy adults, median age 49.5 [36; 59] years; 53 (66.7%) males and 27 (33.3%) females. Headache group consisted of 111 patients with primary headache, median age 54 [45; 64] years, including two subgroups: subgroup 1 (M) of 39 patients; subgroup 2 (TTH) of 72 patients. Carriage of alleles and genotypes rs1801133 and rs1801131 of the MTHFR gene and rs6318 of the HTR2C gene was determined using PCR-RT by TaqMan allelic discrimination technology; (3) Results: A statistically significant association of the carriage of the A allele rs1801133 of the MTHFR gene with the formation of M (p = 0.025) and TTH (p = 0.022), as well as the GA genotype with the development of TTH (p = 0.024) was revealed. Carriage of the G allele and the TG and GG genotypes of the MTHFR gene, associated with a decreased activity of the MTHFR enzyme, does not affect the development of primary headache. A statistically significant association was revealed between the carriage of the heterozygous GC genotype (rs6318) of the HTR2C gene and the formation of M (p = 0.013); (4) Conclusions: Carriage of the A allele (OR 1.77; 95% CI 1.09-2.89) and the GA genotype (OR 2.24; 95% CI 1.17-4.29) rs1801133 of the MTHFR gene is a risk factor for the development of TTH (p <0.05). Carriage of the A allele rs1801133 of the MTHFR gene is a risk factor for the development of M (OR 1.97; 95% CI 1.08-3.57; p <0.05). Carriage of the variant G allele and rs1801131 GT and GG genotypes associated with reduced activity of the MTHFR enzyme does not affect the development of primary headache. In the control group, the prevalence of the T allele associated with normal enzymatic activity was noted (p = 0.024). Carriage of the heterozygous genotype CG SNV rs6318 of the HTR2C gene increases the risk of developing migraine by 3.6 times.