PURPOSE: The diagnosis and management of dry eye disease (DED) could be complicated by the discordance between DED-related symptoms and signs. We performed a cross-sectional study to investigate the factors of and develop predictive models for the discrepancy in DED symptomatology. METHODS: We used data from 3455 participants, 21 to 89 years old, from the Sjögrens International Collaborative Clinical Alliance study. We performed a multivariable stepwise linear regression model with backward elimination and Bayesian information criteria to select predictors for the discordance in DES symptomatology, which was defined as the difference between the rank score of Ocular Surface Disease Index 6 (OSDI-6) and the rank score of ocular staining score (OSS). RESULTS: Ten predictors, such as vitality, immunomodulating drugs, sensory symptoms, and ethnicity, remained in the final models, achieving an adjusted R2 (aR2) of 0.35 (95% confidence interval [CI], 0.32-0.39). Specifically, medication use explained 19% (95% CI, 0.17-0.22) of the variance in the outcome, followed by medical history (aR2 = 0.18; 95% CI, 0.15-0.21). Health-related quality of life contributed 16% to the variance in the outcome (95% CI, 0.13-0.19), and, last, demographics contributed 11% (95% CI, 0.09-0.13). CONCLUSIONS: Our results suggest that individuals of Asian descent and those using immunomodulating medications often present with severe ocular signs that necessitate regular ophthalmological evaluations, even in the absence of proportionate ocular symptoms. Additionally, ocular symptoms, when accompanied by abnormal sensations in other parts of the body, could indicate systemic conditions that require further investigation and medical care.