Light absorption in tissue is generally decreased when chromophores are spatially concentrated rather than being homogeneously distributed. In tissue, this applies to hemoglobin located in blood vessels (vessel packaging). In this paper, the diffusely reflected light from 41 tissue models with discrete blood vessels with diameters ranging from 6.25 to 100 μm were simulated using the Monte Carlo technique. A reverse engineering approach was then utilized to find the model that had an optimal spectral fit to each of the simulated models. The average vessel diameter was one fitting parameter in the adaptive model. The estimated vessel diameter from the optimal fit model was compared to the known diameter from the simulated models. Two different methods to calculate the vessel packaging effect were used, one existing based on a simple analytic expression and a new method based on path length distributions. Both methods had similar performance. For the new method, the absolute RMS deviation of the estimated vessel diameter was 5.5 μm for vessel diameters ≤ 25 μm, and the relative RMS deviation was 21 % for vessel diameters > 25 μm.© (2011) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.