For the detection of Cefixime trihydrate, a straight forward, accurate, precise, and reliable reverse phase high performance liquid chromatography (RP-HPLC) approach has been devised and tested. Drug was resolved on a C18 column, utilizing mobile phase of Triethylamine: Methanol: Acetonitrile: Water (2:10:20:68 V/V%). The mobile phase was degassed by Sonication (10 min) and filtered under vacuum just before HPLC analysis. The flow rate used to provide mobile phase was 1.0 mL/min. Ultra violet detection was carried out at 291 nm. The drug exhibited a peak at retention time 1.547 min. The calibration curve was linear in the range of 2-12 μg/mL and coefficient of regression was found to be 0.9995. The mean percentage recoveries (S.D) for lower intermediate and higher concentrations were found to be 100.0093±0.02837, 100.00±0.00 and 100.0458±0.02178 respectively. With a relative standard deviation (RSD) for intra and inter-day precision of 1.0 over the specified concentration range, the method was determined to be reproducible. The method was successfully applied to the determination of quantity of medicine in SMEDDS formulation of Cefixime trihydrate, it can be very useful and an alternate to perform the stability studies.