Statement of problem: Denture-related mucosal lesions have been broadly studied. However, no consensus has been reached regarding the risk factors associated with these lesions, and few studies have used multivariable analysis to determine the relative significance of different risks. Purpose: The purpose of this study was to determine the relationship between systemic, local, and denture factors on the risk of denture-related oral mucosal lesions in an elderly population by using multivariable analysis. Material and methods: Eighty-four elderly denture wearers recruited from geriatric residences and day care centers participated in this cross-sectional study. All data were obtained by means of a questionnaire-interview, a physical examination, and complementary tests. Bivariate relationship and multiple logistic regression analyses were performed (α=.05). Results: Angular cheilitis (34%), traumatic ulcers (15%), and denture stomatitis (14%) were the 3 most common lesions, and the prevalence of at least 1 denture-related mucosal lesion was 54%. The presence of denture stomatitis was related to low saliva pH, never having smoked, and regular sugar consumption. Angular cheilitis was associated with age, complete edentulism, the presence of oral Candida, a lack of denture stability, and a reduced occlusal vertical dimension. The presence of traumatic ulcers was related to a resorbed residual alveolar ridge. The presence of at least 1 lesion was associated with poor masticatory efficiency, being resident in a care facility, oral Candida, and a lack of denture stability. Conclusions: Several systemic, local, and denture-related characteristics are independent risk factors for denture-related mucosal lesions in an elderly population