Three rapid, sensitive and selective analytical methods were developed for the determination of clonidine hydrochloride and its related substance: 2,6-dichloroaniline in a mixture of both. The first method depends on derivative-ratio spectrophotometry where the first derivative signals of the ratio spectra at 228.4 nm (Δλ = 2 nm) were selected to determine clonidine hydrochloride. The second method is based on measuring the first derivative response of 2,6-dichloroaniline at 300.8 nm with no interference from intact clonidine hydrochloride. In the third method, 2,6-dichloroaniline was determined via diazotization and coupling with N-(1-naphthyl) ethylenediamine to yield a colored azo dye which was measured at 498 nm. Various parameters affecting each method were studied and optimized. The proposed methods were validated according to USP guidelines concerning linearity, ranges, accuracy,precision, detection and quantification limits. The derivative-ratio spectrophotometric method was applied to the analysis of clonidine hydrochloride in tablets and the results were found in good agreement with those of the USP XXX HPLC procedure, while both the second and third methods permitted the selective analysis of 2,6-dichloroaniline in clonidine hydrochloride raw material.