The antimicrobial activities of some cationic amphipathic cyclooctapeptides in combination with select antibiotics are investigated. Accordingly, cyclooctapeptides (CPs 1-11) derived from the sequence cyclo[Leu-D-Leu-Leu-D-Leu-Lys-DLys-Lys-D-Lys] were tested against Escherichia coli and Staphylococcus aureus. Synergistic effects were evaluated in combination with tetracycline, chloramphenicol, oflaxacin, rifampicin, colistin, clindamycin, and vancomycin by the checkerboard titration assay. The results show that these cyclooctapeptides are fast acting bactericidals and are comparable to the related a-helical peptides in their activities. Significantly, some of these cyclooctapeptides exert selective synergistic effects in combination with the bacteriostatic tetracycline against S. aureus; a greater than 4-fold decrease in the minimum inhibition concentration was observed. Their synergism with the other evaluated antibiotics was generally partial or additive. Cationic amphipathic cyclooctapeptides in combination with some antibiotics could offer a possible solution to the increasing antimicrobial resistance predicament.