Summary Background  Recent studies suggest a role for the endocannabinoid system, including fatty acid amide hydrolase (FAAH), in intestinal inflammation. Aim  To analyse FAAH expression and the FAAH 385 C/A (p.Pro129Thr; rs324420) single nucleotide polymorphism (SNP) in‐patients with Crohn’s disease (CD) and ulcerative colitis (UC). Patients and methods  Genomic DNA from 1008 individuals (CD: n = 435; UC: n = 167; controls: n = 406) was analysed for the FAAH 385 C/A SNP. We determined FAAH mRNA expression by quantitative PCR in CD and UC lesions as well as in intestinal epithelial cells (IECs). Results  There were no significant differences regarding the frequency of this SNP in the three study groups (CD, UC, controls). However, CD patients homozygous for the FAAH p.Pro129Thr polymorphism were more likely to develop a severe disease phenotype associated with fistulas (P = 0.03, OR 3.12, 95% CI 1.08–8.98) and extra‐intestinal manifestations (P = 0.005, OR 4.29, CI 1.49–12.35). In UC, homozygous carriers had an earlier disease onset than wild‐type carriers (P = 0.01). FAAH mRNA expression correlated with IL‐8 mRNA expression in CD lesions (r = 0.53). However, pro‐inflammatory stimuli did not significantly increase FAAH mRNA expression in IECs. Conclusion  The FAAH p.Pro129Thr polymorphism may modulate the CD phenotype.