Background Drug-drug interactions (DDIs) are an emerging issue in oncological patients, given the risk of increased toxicities and reduced efficacy from oncological treatments. This is particularly relevant in recurrent-metastatic (RM) head and neck cancer (HNC), where patients are often older, multimorbid, and receiving multiple home medications. While most DDIs are known for chemotherapy and targeted therapies, data on immune checkpoint inhibitors (ICIs) remain limited. Therefore, RM HNC patients represent a target population to investigate DDIs effects on ICIs. Material and Methods We conducted a retrospective, multicenter study to evaluate if polypharmacy affected safety and efficacy in RM HNC patients treated with ICIs, given alone (pembrolizumab or nivolumab) or in combination (combo) with chemotherapy (pembrolizumab-platinum-5-fluoruracil). DDIs were assessed using the Drug-PIN® platform, which provides for each patient two parameters: a Drug-PIN score, i.e. a continuous variable - the greater the number, the greater the likelihood of DDI; and a Drug-PIN level, with 5 levels ranging from green, meaning no interaction found, to red, meaning high potential for interaction. The relationship between Drug-PIN parameters and immune-related adverse events (irAEs) was tested using Student’s t-test. The correlation between Drug-PIN parameters and patients’ survival was assessed with the Kaplan-Meier method. Results We analysed 180 RM HNC (128 males) patients treated between June 2017 and July 2022 with ICIs (49 pembrolizumab alone, 89 nivolumab alone, 42 combo) at three different institutions. The median age was 65 years old (range: 33-89). Every patient took a median of 5 medications (0-15). Median Charlson Comorbidity Index score was 8 (2-14). IrAEs of any grade were observed in 55 patients (31%). Median PFS and OS were 5.9 and 6.5 months for pembrolizumab alone, 7.8 and 11.1 months for combo, 5 and 11.4 months for nivolumab. Median Drug-PIN score was 39.4 (0-214,3); Drug-PIN levels were green, light yellow, dark yellow, orange and red in 56, 27, 32, 9, 56 pts, respectively. Dichotomizing patients according to median Drug-PIN score, no difference was found in irAEs incidence (p 0.48), PFS (p. 0.82), or OS (p 0.89). No differences in irAEs incidence or in survival outcomes could be elucidated by stratifying patients according to Drug-PIN levels. Conclusions ICIs safety and efficacy in the treatment of RM HNC seem not to be affected by polypharmacy and DDIs.