Patients with metastatic or unresectable (advanced) pheochromocytoma or paraganglioma (PPGL) have poor prognoses and few treatment options. This multicenter, phase 2 trial evaluated the efficacy and safety of high-specific-activity I-131 meta-iodobenzylguanidine (HSA I-131 MIBG) in patients with advanced PPGL. <b>Methods:</b> In this open-label, single-arm study, 81 PPGL patients were screened for enrollment, and 74 received a treatment-planning dose of HSA I-131 MIBG. 68 patients with advanced PPGL received at least one therapeutic dose (~18.5 GBq) of HSA I-131 MIBG intravenously. The primary endpoint was the proportion of patients with at least a 50% reduction in baseline antihypertensive medication use lasting at least 6 months. Secondary endpoints included objective tumor response as assessed by Response Evaluation Criteria in Solid Tumors version 1.0; biochemical tumor marker response; overall survival (OS); and safety. <b>Results:</b> Of the 68 patients who received at least one therapeutic dose of HSA I-131 MIBG, 17 (25%; 95% CI, 16–37%) had a durable reduction in baseline antihypertensive medication use. Among 64 patients with evaluable disease, 59 (92%) had a partial response or stable disease as the best objective response within 12 months. Decreases in elevated (≥1.5 times the upper limit of normal (ULN) at baseline) serum CgA levels were observed with confirmed complete and partial responses 12 months after treatment in 19 of 28 patients (68%). The median OS duration was 36.7 months (95% CI, 29.9–49.1 months). The most common treatment-emergent adverse events were nausea, myelosuppression, and fatigue. No patients had drug-related acute hypertensive events during or after the administration of HSA I-131 MIBG. <b>Conclusion:</b> HSA I-131 MIBG offers multiple benefits, including sustained blood pressure control and tumor response in PPGL patients.