ABSTRACTBackgroundThere is a paucity of research on the effects of commonly used substances, such as cannabis and other drugs, on quality of life as a contributor to head and neck cancer (HNC) prognosis. We examined associations between non‐alcohol or tobacco substance use (cannabis and other illicit drug) and self‐reported quality of life in patients with HNC prior to starting treatment.MethodsThis was a cross‐sectional study of patients who presented for routine psych‐oncologevaluation prior to treatment between 11/2015 and 9/2022. Primary exposures were cannabis use (never, past, or current users) and current illicit drug use (yes/no). The primary outcome measure was the Functional Assessment of Cancer Therapy—Head and Neck (FACT‐HN) subscales (physical, social/family, functional and emotional). Linear regression models examined associations between pretreatment substance use and FACT‐HN subscales adjusting for demographic, socioeconomic, and clinical factors.ResultsOf 570 patients, 13.9% endorsed current cannabis and 13.9% current illicit drug use. The mean (SD) scores for FACT‐HN subscales were physical well‐being = 22.8 (5.0), social well‐being = 22.7 (5.5), emotional well‐being = 17.5 (4.5), and functional well‐being = 18.7 (6.9). In the adjusted models, cannabis use was not independently associated with any FACT‐HN subscales. However, patients who currently used illicit drugs reported worse emotional well‐being (β = −1.32; 95% CI −2.45 to −0.20). No independent association was found between current illicit drug use and other subscales (physical, social, and functional).ConclusionsIllicit drug use, but not cannabis use, is negatively associated with pretreatment emotional well‐being in patients with HNC. Further research exploring the relationships between longitudinal cannabis and illicit drug use and methods of consumption on QoL and cancer outcomes in patients with head and neck cancer is warranted.