PURPOSE: Perianal manifestations of Crohn’s Disease (CD) are common and have a significant effect on disease morbidity and patient quality of life. Recent studies suggest that perianal CD may be a distinct phenotype and as such may be associated with specific susceptibility genes and environmental factors. The objective of this study was to examine the relationship between genotype and phenotype in perianal CD. METHODS: Review of a prospectively maintained, IRB-approved institutional database of patients with CD was performed for phenotypic data on patients with and without perianal CD. Genotype data was available for disease associated risk alleles for NOD2, IBD5, ATG16L1, IRGM, and IL23R. Univariate analysis was performed to evaluate differences in genotype and phenotype frequencies between patients with and without perianal CD. Statistical analysis was performed using chi square analysis with significance set at p<0.05. RESULTS: Of 710 patients, 236 (33%) were identified as having perianal CD. There was no difference between patients with and without perianal CD with respect to gender, race, age at diagnosis, family history of IBD, and current or past smoking. Patients with perianal CD were significantly more likely to have received anti-TNF therapy than patients without perianal CD (OR 2.28, 95% CI 1.51-3.45, p<0.0001). There was a trend toward increased antibiotic therapy in patients with perianal CD (OR 1.58, 95% CI 0.99-2.54, p=0.06). The presence of rectal disease was significantly higher in patients with perianal CD than patients without perianal CD (odds ratio [OR] 1.65, 95% CI 1.15-2.36, p=0.006). Genotype data was available on 417 patients. There was a trend toward association of perianal CD and IBD5 risk allele IGR2096 (OR 1.56, 95% CI 0.95-2.57, p=0.08). No association was found between perianal CD and the studied risk alleles for NOD2, ATG16L1, IRGM and IL23R. The requirement for fecal diversion was used as a surrogate marker for the severity of perianal CD. Diversion for perianal CD occurred in 42 patients (18%). There was no significant association of diversion for perianal CD and any of the studied risk alleles. Patients who received anti-TNF therapy were less likely to require diversion for perianal CD (OR 0.28, 95% CI 0.13-0.63, p=0.001). CONCLUSION: In patients with CD, there is a significant association between rectal involvement and the presence of perianal disease. There is a trend toward association of perianal CD and the presence of IBD5 risk alleles. Anti-TNF therapy is associated with a reduced need for fecal diversion in perianal CD.