Epilepsy is a common complex neurological disorder, and some forms are resistant to drug treatment. The HCN1/HCN2 genes encode hyperpolarization‐activated cyclic nucleotide‐gated channels, which play important roles in the electrophysiology of neurons. We investigated the association between HCN1/HCN2 variants and drug resistance or the risk of genetic generalized epilepsies (GGEs). We used matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry to assess nine variants of HCN1/HCN2 in 284 healthy participants and 483 GGEs (279 drug‐responsive, 204 drug‐resistant). Frequencies of HCN2 rs7255568 and rs3752158 G alleles differed in GGEs and in controls (p=0.039, p=0.027, respectively). The frequency of HCN2 haplotype (CAC) was higher in patients than controls (p=0.046). The frequency of the HCN1 rs10462087 CC+CT genotype was lower in patients with childhood absence epilepsy (CAE) than controls (p=0.047). Rs7255568 was associated with the risk of CAE (p=0.028) and juvenile myoclonic epilepsy (JME) (p=0.02). Rs3752158 was associated with the risk of generalized tonic‐clonic seizures, JME, and febrile seizures (all p<0.05). The frequency of the HCN2 haplotype (CAC) was higher in patients with JME (p=0.015) and in those with febrile seizures (p=0.024) than in controls. No significant association was found between HCN1/HCN2 alleles, genotypes or haplotypes, and drug resistance in patients. After Bonferroni's multiple comparisons correction, only the HCN2 rs3752158 C allele and GC+CC genotype frequencies in patients with JME were higher than those in controls (19.2% vs. 11.6%, odds ratio (OR)=1.71, 95% CI = 1.18‐2.32), p=0.004<0.05/9; 36% vs. 22.2%, OR=1.62(1.18‐2.23), p=0.003<0.05/9). Our study suggests that HCN2 rs3752158 is involved in the susceptibility to JME. This article is protected by copyright. All rights reserved.