PURPOSE: To determine correlations between lipids in the fluid reservoir (FR) and the severity of midday fogging (MDF) in scleral lens (SL) wear. METHODS: SL neophytes were recruited to wear custom SL for 4 days, examined after 8 hours on days 1 and 4. Lens vault and MDF were quantified from anterior segment optical coherence tomography (AS-OCT), and the FR was collected and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Relative abundance of lipids was compared to MDF scores using nonparametric correlation testing (Spearman rank). Ocular surface and SL fitting characteristics (lens vault, fitting curves) were likewise compared to MDF. RESULTS: Thirteen participants (26 eyes, 69% female, 28 ± 9 years old) were included in this study. MDF severity after 8 hours of SL wear was 33 ± 29 units on day 1 and 28 ± 24 units on day 4 (r = .94; P < 0.01). Twelve samples were analyzed using LC-MS/MS, and a total of 170 distinct lipid species were detected. The lipid classes with greatest correlation to MDF were the wax esters (r = .73, P = 0.01), cholesteryl esters (r = .59; P = 0.049), and triacylglycerols (r = .64, P = 0.03). Polar lipids were observed abundantly in all samples. None of the measured ocular surface or fitting outcomes were correlated to MDF. CONCLUSIONS: Nonpolar lipids were the greatest contributors to MDF among these normal participants. Polar lipids may be due to cellular debris, although they do not appear contributory to MDF.