SummaryBackgroundNOD2/CARD15 gene variants have not been universally associated with stricturing behaviour in Crohn's disease. Other behaviour modifying genes could explain these results.AimTo study the combined influence of NOD2/CARD15 variants and 4G/4G genotype of type‐1 plasminogen activator inhibitor (PAI‐1) gene on Crohn's disease behaviour.MethodsOne hundred and seventy Crohn's disease patients were studied prospectively, with a mean follow‐up of 7± 6 years. Disease behaviour was registered by using two criteria: the Vienna classification and a non‐hierarchical classification based on the behavioural Vienna categories.ResultsIn the multivariate analysis for stricturing behaviour according to the Vienna categories, only absence of colonic disease (OR, 4.0; 95% CI: 1.49–11.1; P = 0.006) was an independent predictive factor. However, in the multivariate analysis for stricturing disease applying a non‐hierarchical criteria, ileal disease (OR, 4.19; 95% CI: 1.30–13.5; P = 0.01), and carrying both NOD2/CARD15 variants and the 4G/4G PAI‐1 genotype (OR, 5.02; 95% CI: 1.44–17.48; P = 0.01) were independent predictive factors. In the multivariate analysis for penetrating behaviour, the 4G/4G PAI‐1 (OR, 3.10; 95% CI: 1.54–6.23; P = 0.001) and male sex (OR, 2.44; 95% CI: 1.30–4.60; P = 0.005) were independent predictive factors irrespective of criteria applied.ConclusionsCombined PAI‐1 and NOD2/CARD15 genotyping predict complicated Crohn's disease. Patients with these variants could benefit from early interventions.