Background External auditory canal cholesteatoma (EACC) is a chronic inflammation of the bony ear meatus. Its etiology is not clearly understood. Other than surgical intervention, conservative methods are investigated for different cholesteatomas. Inducing apoptosis seems to be an appropriate strategy. Sulindac sulfone is a new class of targeted and pro-apoptotic drugs. It provokes apoptosis by inducing phosphorylation of β-catenin, which is a multifunctional protein in the cell-cell adhesion complex. Methods EACC-cell cultures were incubated with different concentrations of sulindac sulfone (400 and 800 μmol). After 16, 24, and 48 h, β-catenin concentrations were determined by ELISA, Western blot, and immunohistochemical analysis. Results After 48 h incubation with 400 μmol sulindac sulfone, the average level of β-catenin showed a decrease of 46% (0.004337 μg/mL) from those determined at 16 h with the same concentration of sulindac sulfone. At 800 μmol sulindac sulfone, the treated cell culture showed a reduction of 66.2% (0.003443 μg/mL). Comparing total protein content and the fraction of β-catenin at different points in time, the concentration of β-catenin decreased in both EACC cell cultures, 400 μmol (minus 63%) and 800 μmol (minus 81%). Conclusions The results presented in this paper are the first to demonstrate the chemopreventive effects of the agent sulindac sulfone on cholesteatomas. The greatest decrease of β-catenin was observed between 16 and 24 h incubation. The inhibitory effect of sulindac sulfone as a local treatment seems to be a useful additional tool for nonsurgical approach to the therapy of EACCs.