Radionuclide therapy targeting prostate-specific membrane antigen (PSMA) is a promising option for metastatic castration-resistant prostate cancer. Clinical experience using Lu or Ac has demonstrated encouraging treatment responses; however, responses are not durable. Dual-isotope combinations, or "tandem" approaches, may improve tolerability while retaining a high tumor dose. In this study, we directly compared α- versus β-particle treatment, as well as a combination thereof, at different stages of disease in a murine model of disseminated prostate cancer. First, to determine comparable injected activities from Lu- and Ac-PSMA-617, ex vivo biodistribution studies were performed at 5 time points after treatment of C4-2 subcutaneous tumor-bearing NSG mice. To establish a more representative model of metastatic prostate cancer, NSG mice were inoculated with luciferase-expressing C4-2 cells in the left ventricle, leading to disseminated visceral and bone lesions. At either 3 or 5 wk after inoculation, the mice were treated with equivalent tumor dose-depositing activities of Lu- or Ac-PSMA-617 alone or in combination (35 MBq of Lu, 40 kBq of Ac, or 17 MBq of Lu + 20 kBq Ac; 10/group). Disease burden was assessed by weekly bioluminescence imaging. Treatment efficacy was evaluated using whole-body tumor burden and overall survival. The ex vivo biodistribution studies revealed that 35 MBq of Lu and 40 kBq of Ac yield equivalent absorbed tumor doses in a subcutaneous C4-2 model. The disease burden of mice treated at 3 wk after inoculation (microscopic disease) with Lu was not significantly different from that of untreated mice. However, Ac-PSMA-617 both as a single agent and in combination with Lu (17 MBq of Lu + 20 kBq of Ac) were associated with significant whole-body tumor growth retardation and survival benefit (overall survival, 8.3 wk for nontreatment, 9.4 wk for Lu, 15.3 wk for Ac alone, and 14.1 wk for tandem therapy). When treated at 5 wk after inoculation (macroscopic disease), all treatment groups showed retarded tumor growth and improved survival, with no significant differences between Ac alone and administration of half the Ac activity in tandem with Lu (overall survival, 7.9 wk for nontreatment, 10.3 wk for Lu, 14.6 wk for Ac alone, and 13.2 wk for tandem therapy). Treatment of a disseminated model of prostate cancer with simultaneous Ac- and Lu-PSMA-617 results in significantly decreased tumor growth compared with Lu, which was ineffective as a single agent against microscopic lesions. Mice treated later in the disease progression and bearing macroscopic, millimeter-sized lesions experienced significant tumor growth retardation and survival benefit in both monoisotopic and tandem regimens of Lu and Ac. Although the greatest benefits were observed with the single agent Ac, the tandem arm experienced no significant difference in disease burden or survival benefit, suggesting that the reduced activity of Ac was adequately compensated in the tandem arm. The superior therapeutic efficacy of Ac in this model suggests a preference for α-emitters alone, or possibly in combination, in the microscopic disease setting.