Interferon-alpha (IFN-alpha) is recommended in neuroendocrine tumors (NET). Malignant pheochromocytoma and paragangliomas (MPPGLs) constitute a rare subgroup of NET with few treatment options. IFN-alpha efficacy in patients with MPPGLs was evaluated in a single-center retrospective study. Progression-free survival (PFS) was the primary endpoint according to RECIST 1.1 and/or PERCIST 1.0, and response rate, safety, and symptomatic efficacy were secondary endpoints. Fourteen patients received peginterferon alfa-2a (90 to 180 μg/week) or interferon alfa-2b (1.5 to 3 million units × 3/week) at our institution between December 2005 and February 2014 as the first (n = 7), second (n = 3), or subsequent line (n = 4) of treatment. Most of the patients had a slowly progressive disease before IFN-alpha initiation. Eight patients were men (57%); the median age was 44. At the beginning of treatment, 12 patients had progressive disease demonstrated by FDG-PET (n = 9), MIBG (n = 1), or CT scan (n = 2). Most of the patients treated (64%) had metastatic disease limited to or predominantly located in the bones. During IFN-alpha therapy, bone-directed loco-regional treatments were performed in 9 patients (range 1-4). Median PFS was 17.2 months (95% CI [12.1-58.3]). We observed 3 partial metabolic responses, 9 stable diseases, and 2 progressive diseases. No partial response according to RECIST 1.1 was observed. Symptomatic relief of pain, headaches, diarrhea, or sweating occurred in 6 out of 10 symptomatic pts. Most frequent all grade IFN-α-related toxicities were asthenia (n = 10), lymphopenia (n = 7), thrombopenia (n = 6), and anemia (n = 5). Median overall survival was 7.5 years (95% CI [4-NR]). This study suggests symptomatic response and tumor control effect with interferon-alpha in progressive MPPGLs.