Diffuse optical imaging is an effective technique for noninvasive functional brain imaging. However, the measurements respond to systemic hemodynamic fluctuations caused by the cardiac cycle, respiration, and blood pressure, which may obscure or overwhelm the desired stimulus-evoked response. Previous work on this problem employed temporal filtering, estimation of systemic effects from background pixels, or modeling of interference signals with predefined basis functions, with some success. However, weak signals are still lost in the interference, and other complementary methods are desirable. We use the spatial behavior of measured baseline signals to identify the interference subspaces. We then project signals components in this subspace out of the stimulation data. In doing so, we assume that systemic interference components will be more global spatially, with higher energy, than the stimulus-evoked signals of interest. Thus, the eigenvectors corresponding to the largest eigenvalues of an appropriate correlation matrix form the basis for an interference subspace. By projecting the data onto the orthogonal nullspace of these eigenvectors, we can obtain more localized response, as reflected in improved contrast-to-noise ratio and correlation coefficient maps. © 2005 Society of Photo-Optical Instrumentation Engineers.