Abstract We determined the molecular haplotypes of the HLA‐A, HLA‐C and HLA‐B loci and the MHC class I‐B‐related (MIB) microsatellite in 179 unrelated psoriatic patients (72 familial cases) and in 120 controls. The HLA‐A*3002‐Cw*0501‐B*1801‐MIB1 haplotype showed a strong negative association with psoriasis vulgaris (PV) and in particular with familial PV, revealing the presence of a PV‐protective gene. Analysis of association and linkage disequilibrium of the single alleles and the various two‐three‐four‐locus segments of this haplotype indicated the presence of a protective gene telomeric to the HLA‐C locus. This finding was confirmed in 13 informative multiplex PV families, in which at least one parent carried the EH18.2 haplotype. In two families, an affected sibling presented HLA‐A/C recombination on the EH18.2 haplotype. A study of 12 polymorphic microsatellites in all members of the informative families, 145 PV patients, 120 controls and 32 EH18.2 homozygous healthy individuals demonstrated that the protection conferred by the EH18.2 haplotype lies within a 170 kb interval between the C143 and C244 loci, most probably in a 60 kb segment between the C132 and C244 loci.