OBJECTIVE To examine the relationship between central lens thickness and central corneal edema during short-term closed eye scleral lens wear. METHODS Nine participants (mean age 30 years) with normal corneas wore scleral lenses (Dk 141) under closed eye conditions on separate days with nominal center thicknesses of 150, 300, 600, and 1,200 μm. Epithelial, stromal, and total corneal edema were measured using high-resolution optical coherence tomography immediately after lens application and after 90 min of wear, before lens removal. Data were corrected for variations in initial fluid reservoir thickness and compared with predictions from theoretical modeling of overnight scleral lens wear. RESULTS Scleral lens-induced central corneal edema was primarily stromal in nature. The mean±standard error of corrected total corneal edema was 4.31%±0.32%, 4.55%±0.42%, 4.92%±0.50%, and 4.83%±0.22% for the 150-, 300-, 600-, and 1,200-μm lenses, respectively. No significant differences in the corrected total corneal edema were observed across all thickness groups (P=0.20). Theoretical modeling of overnight scleral lens wear seemed to overestimate the relative increase in central corneal edema as a function of decreasing lens Dk/t for values lower than 25. CONCLUSIONS The magnitude of scleral lens-induced central corneal edema during short-term closed eye lens wear did not vary significantly with increasing central lens thickness. Theoretical modeling of overnight closed eye scleral lens wear seems to overestimate the effect of increasing lens thickness.