Two reversed-phase high-performance liquid chromatography (RP-HPLC) methods were developed to investigate the degradation of the acid-labile proton-pump-inhibitor omeprazole in organic polymer solutions and aqueous dispersions of enteric coating polymers (Eudragit L-100, S-100, CAP, HP-55, HPMCAS-HF, -LF, and shellac). The overall goal of the study was to determine the influence of the polymer structure on the degradation of omeprazole, i.e., whether the acid structure of the enteric coating polymers caused an instability of the proton pump inhibitor. Moreover, it was investigated whether a difference in omeprazole degradation could be detected between organic polymer solutions and aqueous dispersions. pKa values of the polymers and pH values of the aqueous dispersions were determined to see whether there was a correlation with the extent of degradation of omeprazole induced by enteric polymers. As the polymers containing phthalate moieties are very susceptible to hydrolysis, the influence of free phthalic acid on omeprazole stability was investigated. Finally, the degradation kinetics of omeprazole in organic polymer solutions were determined. Omeprazole degradation is more pronounced in aqueous polymer dispersions than in organic polymer solutions. The influence of organic polymer solutions on the stability of omeprazole depends on the amount of acidic groups in the polymeric structure, whereas the influence of aqueous polymer dispersions depends on the pH value of the dispersion. The amount of free acids present in some polymers as by-products also cause a degradation of the proton pump inhibitor. Among all investigated polymers, shellac showed the least influence on the stability of omeprazole. The decomposition of omeprazole in organic polymer solutions followed first-order kinetics. The decrease of omeprazole peak area in organic polymer solutions was in the order Eudragit L-100> HPMCAS-HF>shellac.