The purpose of this work was to study two methods of degradation of roxithromycin: acidic hydrolysis and photocatalytic degradation under illumination with near-UV light in the presence of the TiO2 photosensitizer. For acidic degradation studies a TLC-densitometric method has been developed using TLC aluminium plates precoated with silica gel F 254 and the mobile phase composed of methanol-acetone-ammonia 25% (1:14:0.1, v/v/v) which gives compact spots for roxithromycin and its degradation products. Photocatalytic degradation studies in the presence of TiO2 were monitored by HPLC. The obtained results have shown that both methods of degradation of roxithromycin are quite efficient. Kinetics of the first order photocatalytic degradation reaction follows the Langmuir-Hinshelwood theory for photocatalytic microheterogeneous systems. The chemical structures of the degradation products obtained during acidic degradation and photocatalytic degradation were suggested based on the UPLC-MS/MS technique. The general mechanisms of both processes were proposed.