ABSTRACT INTRODUCTION Quality of life measurement is an important aspect of comprehensive clinical assessment. It does not have a set definition, but changes according to sociocultural context. Head and neck cancer patients experience substantially decreased health-related quality of life. The Cuban public health system needs to develop its own instrument to measure these patients’ quality of life. OBJECTIVES Construct and validate an instrument to measure quality of life in Cuban patients with nasopharyngeal, laryngeal, oral or mesopharyngeal cancer. METHOD The sample comprised adult patients treated for nasopharyngeal, laryngeal, oral or mesopharyngeal cancer in Cuba’s National Oncology and Radiobiology Institute in 2013 and 2014. To construct and validate the instrument, we selected a sample of 520 patients. Initial interviews were held until no substantially new information emerged; 40 patients were selected to participate in focus groups to identify important problems leading to decreased health-related quality of life. Face validity of the preliminary questionnaire was assessed with 40 patients. Internal consistency and validity were assessed with 400 patients. Score stability was assessed with another 40 patients using a test-retest design. There were 24 experts who participated in the process, 15 in the construction phase and 9 in the content validity evaluation of the preliminary version. Assessment of reliability and validity was based on internationally recognized approaches, including Cronbach alpha and empirical verification of convergent, discriminant, clinical and predictive validity. Response burden was also assessed (completion time and item nonresponse). RESULTS A 65-item questionnaire, CV-I0R-CyC-01, was developed and validated, with three domains (physical functioning, psychosocial functioning and family relationships, disease symptoms and treatment side effects) and two ungrouped questions on perceived general health and perceived health-related quality of life. The instrument displayed satisfactory reliability (homogeneity and stability) and validity (face, content, convergent, discriminant, clinical and predictive). Test–retest correlation was strong. Large differences and a downward trend in health-related quality of life across clinical stages and moderate or high standardized response mean values reflect good clinical and predictive validity. Response burden was acceptable (completion time 6.2 minutes, item nonresponse rate 1.3%–3.8%). CONCLUSIONS CV-I0R-CyC-01’s psychometric properties justify its use in clinical trial protocols with patients with nasopharyngeal, laryngeal, oral or mesopharyngeal cancer.