The SLC22A4 and SLC22A5 genes within the IBD5 risk locus encode the organic cation transporters OCTN1 and OCTN2. Two variants, 1672C>T in SLC22A4 and -207G>C in SLC22A5, were shown to alter these genes' functions and were identified as genetic susceptibility factors for Crohn's disease (CD). We pursued to check both putative etiologic variants in an independent population through a case-control study with 309 Spanish CD patients and 408 ethnically matched healthy subjects. Both polymorphisms were found in partial linkage disequilibrium (D'=0.86). The separate analysis of each OCTN variant evidenced no association. However, when the simultaneous presence of mutant variants in both genes was analyzed, an effect on CD susceptibility was observed (P=0.026, odds ratio (OR) (95% confidence interval (CI))=1.59 (1.03-2.45)). The previously described predisposition conferred by the 5q31-risk haplotype increased in the absence of the etiologic 1672T and -207C alleles (P=0.0006, OR (95% CI)=10.14 (1.97-98.04)). Moreover, the risk contributed by these polymorphisms was higher in the IBD5 wild-type population (P=0.003, OR (95% CI)=2.65 (1.32-5.35)), arguing against the exclusive etiological role of the OCTN variants. The haplotype pattern inferred led to the consideration of these variants as susceptibility markers only in a defined genetic context. Our data support the interpretation of the 1672C>T SLC22A4 and -207G>C SLC22A5 polymorphisms as genetic markers of susceptibility/protection haplotypes.