Ceftriaxone is a third generation cephalosporin antibiotic with broad spectrum of activity against Gram-positive and Gram-negative bacteria. It interferes with the peptidoglycan synthesis of bacterial cell wall, thus weakening the cell wall which cannot resist osmotic pressure and ruptures. It is the most widely prescribed antibiotic and there is a possibility of its interactions with other drugs. In present work, drug interactions of ceftriaxone were studied with non-steroidal anti-inflammatory drugs, statins, H2-receptor antagonists, Ca-channel blockers, ACE-inhibitors, quinolone and hydrated salts of essential and trace elements. These interactions were carried out in different buffers using UV/visible spectrophotometry and reversed phase high performance liquid chromatography (RP-HPLC). Prior to interaction studies, assay methods for the simultaneous estimation of ceftriaxone and interacting drugs were developed and validated on UV/visible spectrophotometer and RP-HPLC, which were optimized and then applied to interactions.In order to find out the nature of binding between ceftriaxone and interacting drugs, kinetic studies were carried out.