Abstract Efficacy and safety are two key factors in the selection of orally administered antimicrobial agents. This paper reviews the safety profile of oral cephalosporins, macrolides, and fluoroquinolones. Oral cephalosporins and the macrolides are among the safest classes of antimicrobial agents. The most common adverse events associated with oral cephalosporins are hypersensitivity reactions, which occur in 0.7% to 10% of patients. Approximately 5% to 10% of patients with hypersensitivity reactions to penicillin have cross-reactions (usually rash) with oral cephalosporin therapy. There do not appear to be major differences in toxicity among individual oral cephalosporins. The most common adverse event associated with the macrolides is gastrointestinal distress, particularly erythromycin at dosages >4 gm/day. Erythromycin should not be administered intramuscularly because it causes severe local pain. Drug interactions are among the most serious adverse events associated with macrolide therapy. These drugs may inhibit other drugs such as theophylline and carbamazepine, which are metabolized through the liver cytochrome P 450 pathway. If administered concomitantly, serum concentrations of these agents should be monitored closely. Erythromycin inhibits cyclosporin metabolism. Fluoroquinolones also have an excellent safety profile. The most common adverse events are gastrointestinal disturbances, which occur in 2% to 8% of patients. Approximately 1% to 4% of patients experience central nervous system complications. Fluoroquinolones have been shown to cause cartilage erosion in young animals and are not approved for pediatric use in the United States. Some drug interactions may also occur with fluoroquinolone use. In summary, the oral cephalosporins, macrolides, and fluoroquinolones are remarkably safe and effective antimicrobial agents.