<b><i>Objectives:</i></b> This study evaluates maintenance cetuximab administered every 2 weeks (q2w) after chemotherapy plus cetuximab as first-line treatment in a series of patients with head and neck squamous cell cancer and compares the results with those obtained in a historical control group of patients receiving weekly cetuximab. <b><i>Methods:</i></b> After chemotherapy plus cetuximab as first-line treatment, in Group A, 36 patients enrolled from October 2016 to November 2017, received biweekly cetuximab, administered at 500 mg/m². Group B was a control group of patients treated at our institution from August 2015 to September 2016 and received weekly infusion of cetuximab at 250 mg/m². <b><i>Results:</i></b> Confirmed overall response rates were, respectively, 19% for Group A and 17% for Group B according to intention-to-treat analysis. During the maintenance treatment, median progression-free survival (PFS) and median overall survival (OS) were similar for both groups (PFS, 4.8 and 4.4 months; OS, 9.0 and 7.9 months; in Groups A and B, respectively). The most common adverse events among treated subjects included fatigue, rash, and hypomagnesemia. <b><i>Conclusion:</i></b> Maintenance therapy with simplified biweekly cetuximab is a convenient, effective, and well-tolerated regimen in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.