A rapid and sensitive high performance liquid chromatographic method has been developed , validated and applied for the determination of famotidine and ranitidine.HCl in pharmaceutical preparations.The effects of pH, mobile phase composition and concentration of organic modifiers on retention of the investigated drugs were studied. Famotidine and ranitidine.HCl were chromatographically separated from tablets using two columns of different polarity ; Lichrosorb RP-18 ( 15cm x 4.6mm i.d ) 5μm particle size and Lichrosorb RP-8 (25cm x 4.6mm i.d ) 5-10 μm particle size with mobile phase composed of 20:80 v/v of acetonitrile in 0.2% diethyl amine in water (pH=3). UV detection was set at 270nm for famotidine and 322nm for ranitidine.HCl . The calibration graph was linear in the concentration range of 20-70μg .ml-1 for famotidine and 20-120μg .ml-1 for ranitidine. The RSD% was not more than 0.85% and relative error between -0.75-2.08% indicating a good precision and accuracy. The limits of detection were found to be (1.13) and (0.83)μg.ml-1 for famotidine and ranitidine.HCl respectively with recoveries ranged from 98 to 99% .