Objectives: The impact of optical tissue clearing on optical coherence tomography (OCT) for nail tissue imaging has not been investigated. This study seeks to compare the effects of an emollient and water on visualization of micromorphology and morphometric outcomes. Materials and Methods: Thirty-six healthy nail plates were processed with a fractional CO₂ laser, imaged with OCT, and measured with calipers in duplicates. All samples were reassessed after 12-hour long sequential immersion in water and an emollient (Crodamol™ STS). OCT images were evaluated for thickness and scattering signal of the nail. Results: Emollient-impregnation caused stronger scatter responses (P <.0001) and decreased nail thickness (MD 45 μm, P <.0001) measured on OCT. Caliper-derived measurements were not affected by Crodamol™ (MD 11 μm, P =.5538). Hydration increased nail thickness on OCT (MD 49 μm, P <.0001) but reduced thickness measurements taken with calipers (MD 41 μm, P <.0001). Emollient-impregnation improved visualization of onychocytes compared with dry (P =.0209) and hydrated samples (P <.0001), and reduced occurrence of refractive artifacts (P <.0001). Conclusion: The use of an emollient for OCT imaging can enhance nail tissue visualization without significant effects on caliper measurements. Hydration of nails, in contrast with emollient-impregnation, may lead to disagreement between caliper- and OCT-measured nail thickness and should be practiced cautiously.