Abstract Kilogram-size samples can be analysed via Large Sample Instrumental Neutron Activation Analysis (LS-INAA), a method developed for samples which are inhomogeneous at the scale of a small sampling portion but which are assumed to be macroscopically homogeneous. However, extreme inhomogeneities affecting the total gamma-ray detection efficiency, may severely affect the quality of the analysis. A method has been developed to monitor large activated samples for the presence of such extreme inhomogeneities. In addition, a method has been developed for the determination of the spatial distribution of the induced radioactivity. These methods have been tested using a cylindrical phantom, simulating a large activated sample, with a local inhomogeneity. With a collimated detector, the activity was measured stepwise at 2 cm height intervals and 120 rotation intervals, resulting in 150 gamma-ray spectra at 45 seconds per spectrum. The activity distribution is retrieved from the measured spectra, employing a linear least squares matrix inversion of the detection efficiency matrix. This matrix is based on Monte Carlo computed detector responses and experimentally determined transmission coefficients. It is concluded that the proposed method can be employed in a system for 3D-INAA of large samples.