CARD15 on chromosome 16 is the only IBD susceptibility gene identified among several mapped loci. Its recurrent variants R702W, G908R and L1007fs have shown significant association with Crohn's disease (CD), but not with ulcerative colitis (UC), in different Caucasian populations. We analysed these three variants in 184 CD and 92 UC Italian patients and in 177 healthy controls. L1007fs and G908R were independently associated with CD, while R702W showed a nonsignificant increase. After combining the three variants together, 32.6% of CD patients were positive vs 18.6% of the controls. The association was stronger for homozygotes and compound heterozygotes, OR 13.9 (1.8-108), and weaker but still significant for simple heterozygotes, OR 1.7 (1.0-2.9). An excess of homozygotes/compound heterozygotes also resulted from the comparison with Hardy-Weinberg expectations. Phenotype-genotype correlations were analysed first by univariate logistic regression and then by multivariate analysis, the effect of CARD15 positivity being adjusted according to the status of smoking, familiarity and sex, so as to focus on the predictivity of genetic and environmental risk factors on the clinical phenotype. Significant risk estimates of the CARD15 genotype were obtained for stricturing vs inflammatory behaviour, OR 2.76 (1.2-6.3), and for penetrating behaviour, 2.59 (1.0-6.6), and marginally significant for ileal vs colic location, OR 3.0 (0.9-9.8). Our findings indicate that the association of the CARD15 genotype with behaviour and location of disease holds also for the Italian population.