BACKGROUND: The murine orthotopic oral cavity tumor model allows evaluation of tumor growth and invasion. Currently, serial measurements of tissue growth are difficult to obtain since invasive procedures or animal sacrifice is necessary to evaluate tumor size. High-resolution ultrasound was evaluated as a noninvasive method to monitor tumor size in vivo. METHODS: Sixteen immunodeficient mice, age 9 weeks, were injected transcervically with a human squamous cell carcinoma cell line into the tongue, and tumor volume was assessed by high-frequency ultrasound at 11 days. The animals were subsequently sacrificed and the tumors processed for histology. Tumor size was then calculated by caliper measurement in two dimensions. RESULTS: Tumor dimensions obtained using ultrasound were found to significantly correlate with the histologic measurements (Spearman coefficient 0.90, p < 0.0001). Tumor dimensions were on average larger using ultrasound versus histologic measurements, although this was not significantly different than zero (95% confidence interval -13.96 to 62.37 mm2). CONCLUSIONS: High-resolution ultrasound accurately measures tumor volume in the murine orthotopic oral cavity tumor model without sacrifice.