Psoriasis is a chronic skin disease that results in red and scaly lesions. Several psoriasis susceptibility loci have been identified across the genome, of which PSORS1 on 6p21.3 is predominant. There is an ongoing debate regarding whether the HLA-C allele, Cw*0602, can be considered the major predisposing factor in this region. Investigation of other genes in the PSORS1 region with regard to psoriasis may provide alternate candidates to HLA-C. We have characterized two overlapping genes, SEEK1 and SPR1. SEEK1 encodes two putative protein isoforms: the first being one of 152 amino acids from the full-length splice-isoform (exon 1-6), and the second being one of 100 amino acids from an alternate splice-isoform (exon 1 and 6). SPR1 encodes a highly conserved protein of 134 amino acids, and in addition to characterization of human SPR1 we report the cloning of its orthologs in mouse and pig. Both SEEK1 and SPR1 are expressed in normal and psoriasis skin. In a case-control study, five of the nine single nucleotide polymorphisms (SNPs) found in SEEK1 were associated with psoriasis, while one of the four SNPs found in SPR1 showed association. Testing the Cw*0602 confounding status revealed that two of the SEEK1 SNPs showed Cw*0602-independent association, while the SPR1 SNP showed Cw*0602-dependent association. The second exon of SEEK1, containing the two Cw*0602-independent SNPs, showed the highest concentration of the psoriasis-associating SNPs, but did not appear to be translated.