Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder often complicated by cyst infection. Treatment becomes particularly challenging when the culprit organism is resistant to antibiotics known to sufficiently penetrate cysts. We present the case of a patient with ADPKD and suspected cyst infection caused by group B streptococcus who was treated successfully with levofloxacin and ampicillin. Although data support excellent cyst penetration with ciprofloxacin, its gram-positive antimicrobial activity is marginal. The newer quinolones have added gram-positive activity, but little is known about cyst penetration by these antibiotics. We simultaneously measured cyst and serum levels of levofloxacin and ampicillin and found levofloxacin to penetrate cysts well. Therefore, levofloxacin may be useful in the management of renal cyst infection, particularly for the treatment of gram-positive organisms.