Background and objectives: Panic disorder (PD) is an anxiety disorder characterized by recurrent and unexpected panic attacks along with sudden onset of apprehension, fear or terror. The endocannabinoid system (ECS) has a role in stress recovery, regulating anxiety. The aim of this study was to analyze potential genetic alterations in key ECS targets in patients suffering from panic disorders.Design and methods: We analyzed single nucleotide polymorphisms (SNPs) of the cannabinoid receptors (CNR1; CNR2) and the endocannabinoid hydrolytic enzyme fatty acid amide hydrolase (FAAH) genes in 164 Spanish PD patients and 320 matched controls.Results: No significant differences were observed in the SNPs of the CNR2 and FAAH genes tested. However, when analyzing genotype-by-sex interaction at A592G (rs2501431) and C315T (rs2501432) in the CNR2 gene, the presence of the G-allele in males was associated with a protective haplotype. Genotyping analysis revealed that variants in CNR1 confer vulnerability to PD, with a significantly increased risk associated with the G-allele (rs12720071) and C-allele (rs806368). This finding was consistent when analyzing genotype-by-sex interaction, where females presented a greater PD risk.Conclusions: Polymorphisms at the CNR1 gene may be a risk factor for PD contributing to sex-specific dysfunction in females.