Antibiotics were once proposed as hypercholesterolemic agents although the mechanism is unclear, despite broad implications, including providing an alternative approach to cholesterol reduction, with potential relevance for current trials of antibiotics to reduce cardiovascular disease, and possible confounding of routine diagnostic cholesterol measurements. The effect on serum lipids of antibiotics against aerobes and anaerobes, together with possible mechanisms, was therefore explored. Twenty-two men and women took antibiotics for 10 days (either ciprofloxacin for 13 subjects or metronidazole for 10 subjects), with 10 days control in random order separated by 2-week washout periods. Subjects maintained low-fat diets throughout the study. Blood samples and blood pressure were obtained on days 0 and 10 of each phase with 3-day fecal collections and 12-hour breath gas collections at the end of each phase. The results indicated that metronidazole markedly reduced low-density lipoprotein cholesterol (-14.0 +/- 4.0%, P = .006), oxidized low-density lipoprotein (-23.0 +/- 5.1%, P = .002), and the apolipoprotein B/A-I ratio (-18.0 +/- 2.8%, P < .001), whereas the reduction with ciprofloxacin was less pronounced (apolipoprotein B/A-I, -5.0 +/- 1.8%, P = .017). Neither antibiotic altered C-reactive protein or blood pressure. The low-density lipoprotein cholesterol reduction related to an increase in bifidobacteria (r = -0.46, P = .029), but not to markers of colonic fermentation. We conclude that antibiotics can reduce serum lipids acutely. These effects may confound diagnostic measurements but indicate possible links between colonic microflora and blood lipids and the need to study ways of altering colonic microflora by nonantibiotic means as a potential therapeutic option.