In several investigations of molecular imaging of angiogenic neovasculature using a targeted contrast agent, Renyi entropy I f (r) and a limiting form of Renyi entropy (I f,∞ ) exhibited significantly more sensitivity to subtle changes in scattering architecture than energy-based methods. Many of these studies required the fitting of a cubic spline to backscattered waveforms prior to calculation of entropy either I f (r) or I f,∞. In this study, it is shown that the robustness of I f,∞ may be improved by using a smoothing spline. Results are presented showing the impact of different smoothing parameters. In addition, if smoothing is preceded by low-pass filtering of the waveforms, further improvements may be obtained.