Regularization, filtering, and denoising of biomedical images requires the use of appropriate filters and the adoption of efficient regularization criteria. It has been shown that the Stein’s Unbiased Risk Estimate (SURE) can be used as a proxy for the mean squared error (MSE), thus giving an effective criterion for choosing the regularization amount as to that minimizing SURE. Often, due to the complexity of the adopted filters and solvers, this proxy must be calculated with a Monte Carlo method. In practical biomedical applications, however, images are affected by spatially-varying noise distributions, which must be taken into account. We propose a modification to the Monte Carlo method, called svSURE, that accounts for the spatial variability of the noise variance, and show that it correctly estimates the MSE in such cases.