This study compared contrast-enhanced ultrasound (US) measures of tumor neovascularity with molecular markers of angiogenesis in a human melanoma xenograft model. A total of 14 mice were implanted with a human melanoma cell line (WM-9) in the thigh. After 2 to 3 weeks, a tumor, approximately 12 mm in diameter, developed. The US contrast agent Optison (Mallinckrodt, St. Louis, MO) was injected in a tail vein (dose: 0.4 to 0.6 mL/kg). Power Doppler and pulse-inversion harmonic imaging (HI) were performed with an Elegra scanner (Siemens Medical Systems, Issaquah, WA) and a 7.5 MHz linear array. Frame-rates of 30 Hz and 0.5 Hz (intermittent imaging) were used for pulse-inversion HI. After surgical removal, specimens were sectioned in the same planes as the US images. Immunohistochemical stains for endothelial cells (CD31), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and cyclooxygenase-2 (COX-2) were performed. Two observers graded the stains (for intensity and percent area), and two other observers graded the US imaging modes (for fractional tumor neovascularity) on the same scale from 0 to 3. Of the 14 mice, 4 failed for technical reasons (i.e., n = 10). Linear regressions indicated statistically significant correlations between percent area stained with COX-2 and power Doppler (r = -0.789; p < 0.01), as well as intermittent pulse-inversion HI (r = -0.795; p < 0.05). There was a trend toward significance between percent area stained with VEGF and intermittent pulse-inversion HI (r = -0.720; 0.05 < p < 0.10). No other comparisons were significant. In conclusion, contrast-enhanced US measures of tumor neovascularity in a human melanoma xenograft model appear to provide a noninvasive marker of angiogenesis corresponding to expression of COX-2. However, the sample size of this study is small and, until further studies have been conducted, these conclusions are preliminary.