To determine the reliability of single- and double-zone corneal fluorescent staining compared with five-zone analysis for the prediction of dry eye disease. Prospective study of 510 subjects with dry eye disease characterized using corneal fluorescein staining, Schirmer scores, and tear break-up times. Corneal staining was quantified using Baylor scoring with ROC analysis used to assess predictive power of single- and double-zone compared with five-zone analysis for aqueous, evaporative, and mixed dry eye disease. Double-zone analysis predicted each subtype of dry eye disease investigated. Aqueous disease was predicted by superior/inferior zones (AUCSup/Inf 0.797 versus AUCTotal 0.816), evaporative disease by inferior/central zones (AUCInf/Cen 0.759 versus AUCTotal 0.778), and mixed disease by superior/inferior, inferior/nasal, and inferior/central zones (AUCSup/Inf 0.765, AUCInf/Nas 0.771, AUCInf/Cen 0.778 versus AUCTotal 0.795). Inferior zone analysis predicted aqueous (AUCInf 0.751 versus AUCTotal 0.750), evaporative (AUCInf 0.756 versus AUCTotal 0.752), and mixed (AUCInf 0.831 versus AUCTotal 0.788) dry eye disease with similar efficacy to complete analysis in diabetic individuals. Inferior zone analysis also predicted aqueous disease in rheumatoid arthritis patients (AUCInf 0.804 versus AUCTotal 0.785), whereas superior zone analysis predicted evaporative disease in thyroid disease patients (AUCSup 0.765 versus AUCTotal 0.752). Double-zone corneal staining predicts the presence of dry eye disease with predictive power similar to complete corneal analysis. Additionally, subtypes of dry eye can be predicted by single-zone analysis among patients with diabetes (inferior zone), rheumatoid arthritis (inferior zone), and thyroid disease (superior zone). Clinical characterization of dry eye can thus be hastened by limiting corneal examination to specific zones.