PURPOSE: To determine whether there is an association between gene expression profile and looping extravascular matrix patterns in primary uveal melanomas. DESIGN: Laboratory investigation. METHODS: Formalin-fixed, paraffin-embedded sections from 22 primary uveal melanomas that previously were analyzed by microarray gene expression profiling were stained for periodic acid-Schiff and scored in a masked fashion for the presence of looping extravascular matrix patterns. RESULTS: A strong association was observed between looping patterns and the unfavorable class 2 molecular prognostic signature (P < .001). CONCLUSIONS: Looping extravascular matrix patterns occur almost exclusively in class 2 uveal melanomas. This finding may provide new insights into the pathogenesis and management of uveal melanoma.