BACKGROUND: Intrinsic properties of vehicles used to deliver topical therapies can profoundly impact drug penetration, efficacy, patient acceptance, and treatment adherence. Therefore, advancements in vehicle technology demand sophisticated, quantitative approaches to describe and differentiate topical formulations. The objective of these studies was to quantitatively evaluate spreadability of two topical formulations for the treatment of acne via in vitro rheological measurement (how a substance’s flow characteristics change under applied stress or force) and spreadability on living skin. METHODS: Rheological characteristics (shear-thinning, rigidity, yield stress, and yield strain) of tazarotene 0.045% lotion and trifarotene 0.045% cream were measured using 5 samples of each product. In a clinical split-body study, each formulation was applied to one side of the back of healthy volunteers, and the extent to which each formulation could be spread was measured. RESULTS: Compared to trifarotene cream, tazarotene lotion demonstrated lower mean viscosity, rigidity, and yield stress, and higher yield strain, suggesting a superior spreadability profile. This finding was confirmed in the split-body study of 30 healthy White adults, in which the average area of spread was significantly larger for tazarotene lotion than trifarotene cream (167.0 vs 130.3 cm2; P<0.001). CONCLUSIONS: Rheological assessment effectively predicted the superior spreadability of tazarotene 0.045% lotion versus trifarotene 0.005% cream on living skin. Given the importance of aesthetics of topical formulations, techniques to quantify these properties may have broad implications when developing novel vehicle formulations for dermatology. J Drugs Dermatol. 2022;21(3):250-257. doi:10.36849/JDD.6703.