Cefotaxime (CTX) and HRE 664 (a novel penem antibiotic) possess complementary in vitro properties. Differences can be observed in their antibacterial spectra, their β-lactamase stability and -inhibition, and their affinity to penicillin-binding proteins. These differences suggested that combinations of the cephalosporin and the penem antibiotic would be advantageous and should be studied. The fractional inhibitory concentration values of checkerboard studies confirmed that CTX and HRE 664 act synergistically against various Gram-positive and Gram-negative bacteria. Fixed combinations containing 80% CTX and 20% HRE 664 possess broader antibacterial spectra and in certain cases higher antibacterial activities than each of the components alone. The combinations had improved activity against Staphylococci including methicillin-resistant strains, β-lactamase producing strains of Enterobacter sp. and Bacteroides fragilis. The combination as well as the single antibiotics had only limited activity against Pseudomonas aeruginosa.