Specific extracellular matrix patterns in uveal melanoma are associated with metastatic risk. The laminin-rich composition and dimensions (on the order of a wavelength or less) of these structures suggest that acoustic backscatter might be affected by their presence. In this study, 10-MHz radiofrequency (RF) ultrasound (US) data were acquired before surgical removal of 117 eyes with uveal malignant melanoma. Histologic sections were evaluated for the presence of matrix patterns and acoustic backscatter was characterized using calibrated spectrum analysis. Statistical correlations between acoustic and histologic patterns were determined and linear discriminant analysis (LDA) and radial basis networks (RBN) were used to develop classification models for histologically based risk groups. Statistically significant correlations were found between acoustic parameters and the presence of histologic matrix-rich patterns. Retrospective classification accuracies of 74.4% and 78.6% were obtained with LDA and RBN, respectively. Leave-one-out analyses indicated estimated predictive accuracies of 71.8% and 75.0% for LDA and RBN, respectively.