Background: Mitoxantrone hydrochloride liposomes (PLM60) have been approved for the treatment of relapsed/ refractory peripheral T-cell lymphoma (PTCL) in China. This study evaluated the safety and efficacy of PLM60 in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Methods: Patients with histologically confirmed HNSCC (including nasopharyngeal carcinoma (NPC)) were enrolled. PLM60 was administered at a dose of 20 mg/m2 by intravenous infusion every 21 days (one cycle) with a maximum of eight cycles. The primary objective was to determine the safety and the secondary objective was to assess the efficacy of PLM60 in this setting. Results: A total of 45 patients with a median age of 50 years were enrolled (26 NPC and 19 non-NPC). Eleven patients completed the planned regimen. The most common hematological adverse events (AEs) were anemia (64.4 %), decreased white blood cell count (55.6 %), and decreased lymphocyte count (46.7 %). The most common non-hematologic AE was skin hyperpigmentation (37.8 %). Grade >= 3 AEs occurred in 30 patients (80.0 %), and most were hematologic. Four patients reported AEs leading to death, with two cases assessed as possibly related to the study drug. Of the 37 patients evaluable for efficacy, the overall objective response rate (ORR) was 24.3 % (95 % CI: 11.8-41.2 %) and the disease control rate was 62.2 % (95 % CI: 44.8-77.5 %). The proportion of patients with an overall response was higher in the NPC group (7/25, ORR: 28.0 %) than in the non-NPC group (2/12, ORR: 16.7 %). Conclusions: PLM60 has demonstrated manageable safety and evidence of efficacy in patients with recurrent/ metastatic HNSCC.