A sensitive, rapid, reproducible, easy and precise reverse-phase high-performance liquid chromatographic assay for stability studies of tetracycline hydrochloride (TC.HCl) formulated with different excipients and techniques without using gradient elution, extraction methods, and at ambient temperature has been developed and validated. The method was especially developed for the analysis of TC.HCl and its main degradation product, 4-epi-anhydrotetracycline, due to its toxicity, in samples obtained from stability studies of solid dosage forms (tablets). The influence of the excipients used for the pharmaceutical design of the different tablet formulations and the use of hydroxypropyl-beta-cyclodextrin on the stability were evaluated. A significant improvement of the stability of TC.HCl was found in some tablet formulations. The precision and accuracy of the method was also studied for the encapsulated TC.HCl, and no significant interferences were found. The results obtained suggested that the developed HPLC method is selective and specific for the analysis of TC.HCl samples, and that it can be applied for long-term and accelerated protocols for stability studies.