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Purpose: Prostate-specific membrane antigen (PSMA) targeting radioligands deliver radiation to PSMA-expressing cells. However, the relationship between PSMA levels and intralesion heterogeneity of PSMA expression, and cytotoxic radiation by radioligand therapy (RLT) is unknown. Here we investigate RLT efficacy as function of PSMA levels/cell, and the fraction of PSMA + cells in a tumor., Experimental Design: RM1 cells expressing different levels of PSMA (PSMA - , PSMA + , PSMA ++ , PSMA +++ ; study 1) or a mix of PSMA + and PSMA - RM1 (study 2, 4) or PC-3/PC-3-PIP (study 3) cells at various ratios were injected into mice. Mice received 177 Lu- (studies 1-3) or 225 Ac- (study 4) PSMA617. Tumor growth was monitored. Two days post-RLT, tumors were resected in a subset of mice. Radioligand uptake and DNA damage were quantified., Results: 177 Lu-PSMA617 efficacy increased with increasing PSMA levels (study 1) and fractions of PSMA positive cells (studies 2, 3) in both, the RM1 and PC-3-PIP models. In tumors resected 2 days post-RLT, PSMA expression correlated with 177 Lu-PSMA617 uptake and the degree of DNA damage. Compared with 177 Lu-PSMA617, 225 Ac-PSMA617 improved overall antitumor effectiveness and tended to enhance the differences in therapeutic efficacy between experimental groups., Conclusions: In the current models, both the degree of PSMA expression and the fraction of PSMA + cells correlate with 177 Lu-/ 225 Ac-PSMA617 tumor uptake and DNA damage, and thus, RLT efficacy. Low or heterogeneous PSMA expression represents a resistance mechanism to RLT. See related commentary by Ravi Kumar and Hofman, p. 2774 ., (©2020 American Association for Cancer Research.)