The distinction between Sézary syndrome (SS) and benign erythrodermic inflammatory diseases (EID) is difficult to make both clinically and on skin biopsies, since histomorphology can provide nonspecific results. New markers of circulating malignant Sézary cells have been recently described, especially CD158k/KIR3DL2 and T-plastin, but it has not been yet determined whether they could help in the diagnosis of erythroderma in skin samples. In this study, 13 frozen skin specimens from 10 SS patients and 26 from EID were analyzed for CD158k/KIR3DL2 expression using immunohistochemistry with AZ158 mAb, which also recognizes the monomeric CD158e/KIR3DL1 receptor. Although positive in all SS samples, immunohistochemistry appeared to not reliably discriminate between SS and EID. Therefore in all samples disclosing a significant staining with AZ158 mAb, CD158k/KIR3DL2, CD158e/KIR3DL1 and T-plastin mRNA expression were analyzed on the same skin specimen using conventional and/or quantitative real-time reverse transcription (RT)-PCR. Interestingly, only CD158k/KIR3DL2 transcripts were found to be significantly overexpressed in skin biopsies from patients with SS (P<0.0001), including when normalization to CD3 expression was achieved (P=0.0003). In light of these findings, CD158k/KIR3DL2 transcripts appear to be a unique molecular marker of SS in skin samples, allowing differential diagnosis with benign EID in routine practice.