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The impact of oral rehabilitation on masticatory function and oral health-related quality of life (OHRQoL) may vary with the experience of the individual with tissue loss. Our hypothesis is that patient-centered outcomes vary among adults who have experienced large defects in the maxilla due to congenital or acquired conditions even after oral rehabilitation to restore aesthetics and function. This study compared OHRQoL, perceived masticatory ability, maximum bite force (MBF), and symptoms of pain and depression among subjects with acquired (edentulous maxilla) and congenital (cleft lip and palate) loss of oral tissues in the maxilla after dental treatment. A gender-matched sample (n = 60) of cleft lip and palate (CLP), maxillary denture wearers (DENT) and controls (CONT) was recruited. OHRQoL was assessed using OHIP-14. Chewing was evaluated through a masticatory ability questionnaire and by MBF. The RDC/TMD Axis II questionnaire was used to assess symptoms of pain and depression. Data were analyzed by Fisher's test, Kruskal Wallis test, and Spearman correlation coefficients. CLP showed higher OHIP-14 and depression scores than DENT and CONT (p < 0.05). Sub-analysis by OHIP-14 items (%FOVO) showed higher prevalence of psychological impact for CLP and of functional impacts for DENT. The number of foods difficult to chew, of food textures difficult to chew, and avoided foods were similar between CLP and DENT. OHIP-14, MBF, and depression scores showed significant correlation (p < 0.05). The results suggest that adults with treated CLP or maxillary DENT have chewing impairment and lower MBF than healthy subjects, with different psychological and functional impacts.