Measuring health-related quality of life (HRQoL) facilitates the monitoring and evaluation of the population's health status, and country's public health policies. Studies undertaken in the Republic of Benin on this issue are quite rare. Objective: The objective is to study the level of HRQoL in people with chronic communicable or non-communicable diseases at the Ouémé department in Benin. Method: This is a cross-sectional and analytical survey conducted at this department in 2018. Medical Outcomes Study SF-36 questionnaire was administered to 523 people over 15 years of age who were suffering from chronic disease, and they were selected by the snowball technique. The level of HRQoL defined in three modalities was determined from the four dimensions of each of its physical and mental components. Results: In the Ouémé department, eight chronic diseases were identified and the level of HRQoL appeared higher in rural areas for hypertension, sickle cell disease and sinusitis. In total, 73.8% of people with chronic diseases had high levels of HRQoL. The level of HRQoL was higher in rural areas than in urban areas (85.2% versus 64.8%; p < 0.0001). Interventions on HRQoL at the Ouémé department must take into account the disparities between urban and rural areas.