The paradoxical effect of antibiotics is defined as a substantially reduced bacterial killing at antibiotic levels above the minimal bactericidal concentration in vitro. This phenomenon which was originally described for beta-lactam antibiotics in their reactions against Gram-positive bacteria has later been noted with aminoglycosides against Gram-negatives and other antibiotic-microorganism combinations, indicating a multifaceted background. The clinical significance of the paradoxical effect is unknown. However, the phenomenon can be demonstrated in vitro at levels easily achievable in clinical situations, as illustrated in our own experiments, where clinical isolates of Staphylococcus aureus were tested for a paradoxical effect versus several penicillins. In most strains exhibiting a paradoxical effect, this effect occurred at concentrations as low as 10xMIC. The relationship between paradoxical effect and tolerance is discussed.