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Purpose: To evaluate the oral health-related quality of life (OHRQoL) of individuals diagnosed with Fanconi anemia (FA). Methods: A cross-sectional study was conducted with FA patients from two Brazilian referral centers. Participants underwent a complete dental, periodontal, and oral mucosa examination, as well as assessment of resting salivary flow. The short version of the Oral Health Impact Profile (OHIP-14) questionnaire was administered. Descriptive and bivariate analyses were performed, followed by multivariate analysis to examine the impact of independent variables on OHRQoL. Results: The study included 20 (57.1%) males and 15 (42.9%) females, with a mean age of 18.9 years. Oral leukoplakia (OL) was found in 18 individuals. The overall OHIP-14 score was 9.9 ± 10.5. Individuals aged ≥ 16 years had higher OHIP-14 scores, indicating worse OHRQoL for physical pain (p = 0.007), psychological discomfort (p = 0.001), physical disability (p = 0.03), psychological disability (p = 0.001), handicap (p = 0.004), and overall score (p = 0.007). Females reported more negative OHRQoL than males for physical pain (p = 0.02), psychological discomfort (p = 0.03), psychological disability (p = 0.009), and overall score (p = 0.02). Individuals with OL had an overall OHIP-14 score 1.83 times higher than those without OL (95% CI: 1.02–3.28; p = 0.04). Lower salivary flow correlated with higher overall OHIP-14 scores (95% CI: 0.14–0.84; p = 0.01). Conclusion: This study represents the first attempt to evaluate OHRQoL in individuals with FA. The presence of OL and reduced salivary flow were identified as predictors of a negative impact on OHRQoL. It is imperative to integrate patients' quality of life in the clinical treatment protocols for the FA population. [ABSTRACT FROM AUTHOR]