This work describes a RP-HPLC method for the determination and interaction studies of cefpirome with ACE-inhibitors (captopril, enalapril and lisinopril) in various buffers. The separation and interaction of cefpirome with ACE-inhibitors was achieved on a Purospher Star, C 18 (5μm, 250×4.6mm) column. Mobile phase consisted of methanol: water (80:20, v/v, pH 3.3); however, for the separation of lisinopril, it was modified to methanol–water (40:60, v/v, pH 3.3) and pumped at a flow rate of 1mLmin −1 . In all cases, UV detection was performed at 225nm. Interactions were carried out in physiological pH i.e., pH 1 (simulated gastric juice), 4 (simulated full stomach), 7.4 (blood pH) and 9 (simulated GI), drug contents were analyzed by reverse phase high performance liquid chromatography. Method was found linear in the concentration range of 1.0–50.0μgmL −1 with correlation coefficient (r 2 ) of 0.999. Precision (RSD%) was less than 2.0%, indicating good precision of the method and accuracy was 98.0–100.0%. Furthermore, cefpirome–ACE-inhibitors’ complexes were also synthesized and results were elucidated on the basis of FT-IR, and 1 H NMR. The interaction results show that these interactions are pH dependent and for the co-administration of cefpirome and ACE-inhibitors, a proper interval should be given.