ObjectiveTo investigate orofacial traits and general factors related to oral health‐related quality of life in acromegaly patients.Materials and MethodsA cross‐sectional study with 34 acromegaly patients was conducted. The OHIP‐14 questionnaire was used to assess oral health‐related quality of life scores. To assess orofacial and occlusion morphology, an oral evaluation was performed. Correlation measures, multiple linear regression and a structural equation model (SEM) were used in the statistical analysis.ResultsThe presence of arthrosis (SC = 0.467, SE = 0.155, p = 0.003) and smoking history (SC = 0.459, SE = 0.206, p = 0.026) were associated with a negative impact on oral health‐related quality of life. Mandibular protrusion was related to physical pain (β = 2.74, p = 0.029). Anterior open bite (β = 4.44, p = 0.004) and anterior crossbite (β = 2.61, p = 0.026) were related to psychological disability. Diastema was related to social disability (β = 3.42, p = 0.037) and handicap (β = 2.74, p = 0.044).ConclusionThe findings suggest that smoking, arthrosis and orofacial alterations (mandibular protrusion, open bite, crossbite and diastema) have a negative impact on oral health‐related quality of life in acromegaly patients.