The impact of surfactants on supersaturation of clotrimazole solutions was systematically evaluated. Four clinically relevant surfactants, sodium dodecyl sulfate, vitamin E TPGS, Tween 80, and docusate sodium were studied. The induction time for nucleation and rate of desupersaturation were determined at a supersaturation ratio of 90% amorphous solubility. Measurement was also performed in the presence of predissolved hydroxypropyl methylcellulose acetate succinate to study the effect of surfactant-polymer interaction on desupersaturation. The 4 surfactants showed varied effects on desupersaturation. From supersaturation maintenance perspective, in the presence of hydroxypropyl methylcellulose acetate succinate, the rank order for the 4 surfactants was found to be: docusate sodium > vitamin E TPGS > sodium dodecyl sulfate > Tween 80. Given the importance of maintaining supersaturation and varied effect of surfactants on nucleation kinetics and desupersaturation rate, a careful examination of active pharmaceutical ingredient, polymer and surfactant interaction on an individual basis is recommended for selecting an appropriate surfactant for use in amorphous solid dispersion formulation.