In this study, four different spectrophotometric methods were applied for determination of cimetidine and erythromycin ethylsuccinate drugs in pure form and in their pharmaceutical preparations. The suggested methods are simple, sensitive, accurate, not time consuming and inexpensive. The results showed the following: The first method: Based on the formation of ion pair complex of each drug with bromothymol blue (BTB) as a chromogenic reagent. The formed complexes were extracted with chloroform and their absorbance values were measured at 427.5 nm for cimetidine and 416.5nm for erythromycin ethylsuccinate; against their reagents blanks. Two different methods, univariate method and multivariate method, were used to obtain the optimum conditions for the spectrophotometric determination of the cited drugs via ion pair formation. The Multivariate method involves the simplex optimization in addition to design of experiment (DOE)for the case of cimetidine. The study shows that the optimum conditions for the instantaneous formation of the ion-pair complexes, in aqueous medium, were: solution pH is 5.5 and 4.0 for cimetidine and erythromycin ethylsuccinate respectively, when 0.5 ml of phthalate buffer is used followed by the addition of 1 ml of 0.038% (for cimetidine) and 0.020% (for erythromycin ethylsuccinate)of BTB reagent. Moreover, the influence of different factors affecting the chloroformic extraction of the formed complexes was studied in each case. It was found that 6 min (for the case cimetidine complex) and 3 min (for the case erythromycin ethylsuccinate) shaking with one portion of 5 mL of chloroform was enough for quantitative extraction of the mentioned complexes.