We used calcium concentration data from over 3000 stream and river sites across the contiguous United States to classify ecoregions relative to their risk for Dreissena species invasion. We defined risk based on calcium concentrations as: very low (< 12 mg L−1), low (12–20 mg L−1), moderate (20–28 mg L−1), and high (> 28 mg L−1). Ecoregions comprising 9.4% and 11.3% of land area were classified as very low risk and low risk, respectively. These areas included New England, most of the southeast, and western portions of the Pacific Northwest. High-risk ecoregions comprised 58.9% of land area. Ecoregions with highly variable calcium concentrations comprised 19.8% of land area; none could be classified as moderate risk. The majority of Dreissena occurrences (excluding the Great Lakes) were located in high-risk ecoregions, and most exceptions occurred in highly variable ecoregions. In low-risk ecoregions, mussels occurred in large rivers flowing from high-calcium regions. Our map provides guidance for the allocation of management resources.