There is evidence that nonuniform activity distributions within tumors might cause targeted radionuclide therapy (TRT) to fail. The aim of this study was to investigate the effects of the temporal and spatial behavior of the radioactivity in TRT, focusing on heterogeneous radiopharmaceutical distributions at a multicellular scale. Various activity distributions at the multicellular level from three radionuclides ((32)P, (90)Y, and (131)I) were simulated in cubic matrices (1- and 3-mm side). The in-house software package DOVE was used to calculate dose-rate maps, and survival fractions were calculated taking into account an up-take and a clearance phase. The effect from nonuniform activity distributions was analyzed in terms of dose volume histograms (DVHs), biologically effective dose (BED), and the effective uniform dose (EUD). The fraction of the absorbed dose that is "wasted," without producing a biological effect to the treatment, reaches 60% in the highly nonuniform distributions. For (32)P and (90)Y, the loss of therapeutic effectiveness was shown to be less than for (131)I. However, (90)Y, owing to its shorter physical half-life, presented lower mean BED values in almost every geometry, compared to (32)P and (131)I, and thus was less effective. (131)I, among all geometries, appeared to be more effective in more homogeneous activity distributions and in the 1-mm volume of interest, whereas it was the least effective radionuclide in the more heterogeneous activity distributions. (32)P presented the highest values of EUD, compared to (90)Y and (131)I. The EUD is a unique value that facilitates comparisons between different activity distributions in terms of treatment outcome. This study showed that as the degree of the heterogeneity in the dose distributions increases, the therapy effectiveness worsens. Nonuniform absorbed dose distributions can create a situation in which a fraction of cells are underirradiated, while another fraction of cells is "over-killed."