Background: An important unmet need in treatment options remains for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) previously treated with both platinum-based chemotherapy and anti-PD-1 antibody (PD-1 Ab). Recent retrospective studies suggest that previous treatment with Immune checkpoint inhibitor might augment the efficacy of subsequent chemotherapy. This phase II trial aimed to evaluate the efficacy and safety of paclitaxel plus biweekly cetuximab (PTX+bwCmab) for patients with R/M-HNSCC previously treated with both platinum and PD-1 Ab. Methods: This is a single-arm, multicenter phase II trial. Key eligibility criteria were R/M-HNSCC; previous treatment with both platinum-based chemotherapy and PD-1 Ab; ECOG performance status 0 or 1; measurable disease per RECIST v1.1; and adequate organ function. PTX+bwCmab consisted of weekly paclitaxel 100 mg/m² (days 1, 8, 15) and biweekly cetuximab 500 mg/m² (days 1, 15) with a cycle of 28 days. Primary endpoint was objective response rate (ORR). We set a null hypothesis of 10% and alternative of 30% with a one-sided alfa of 0.05 and power of 90%. Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs) (CTCAE v5.0). Binominal confidence intervals (CIs) for ORR and DCR were estimated by the exact method. Time-to-event analyses were calculated by the Kaplan-Meier method with 95% CIs. Results: Between August 2020 and August 2022, 35 patients were enrolled, of whom 32 were evaluable for response. ORR was 68.7% (95% CI: 49.9-83.8), which met the prespecified criteria for the primary endpoint of ORR. With a median follow-up period for survivors of 16.6 months, median PFS and OS were 5.7 and 13.4 months, respectively. DCR was 93.7% (95% CI: 79.1-99.2). The most common AEs of any grade were skin rash (65%), peripheral nerve neuropathy (45%), neutropenia (40%), fatigue (40%) and paronychia (37%). Grade 3 and 4 adverse events included neutropenia (34%), mucositis (8%), pneumonitis (8%) and febrile neutropenia (5%). These AEs were manageable and no treatment-related death within 30 days was observed. Conclusions: PTX+bwCmab showed highly encouraging efficacy and tolerability in RM-HNSCC patients previously treated with both platinum and PD-1 Ab. Although preliminary, these results suggest that this is a promising treatment option for this hitherto untreatable patient group. Further evaluation is warranted. Clinical trial information: jRCTs051200040.