Osteochondrosis (OC) is a developmental disease that affects growing horses and that severely affects their ability to perform. The genetic basis of its pathogenesis is poorly understood. The aim of the study was to analyze the transcript profile of leukocytes from horses affected with OC. Two transcriptome libraries were constructed from leukocytes of OC‐affected and non–OC‐affected horses using digital gene expression analysis (DGE) and real‐time PCR. Statistical analysis allowed selection of 1,008 tags upregulated in the non–OC‐affected group and 1,545 tags upregulated in the OC‐affected group. Among these genes, 16 regulated genes and 5 housekeeping genes were selected. Metabolic pathways analysis showed an obvious dysregulation of several signaling pathways related to cartilage formation or cartilage repair, including Wnt, Indian hedgehog, and TGF‐beta signaling. Other genes, including ISG, ApoB, MGAT4, and TBC1D9, showed a significantly different expression between groups. These genes may play a role in high carbohydrate diet, abnormal insulin metabolism, or inflammation, mechanisms suspected to be involved in OC. This DGE analysis of the transcript profile of leukocytes from OC‐affected horses demonstrated significant differences in comparison to the control library. These results open new perspectives for the understanding of equine OC. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:965–970, 2010