The pharmacokinetics of ampicillin and dicloxacillin following intravenous injection was studied in a tissue cage model in rabbits. Serum protein binding was 98.6% for dicloxacillin and 46.7% for ampicillin, and there were no major differences between the degree of binding in tissue case fluid. The highly bound dicloxacillin gave lower but more sustained levels in tissue cage fluid than ampicillin, and showed a very long elimination half-life. The findings suggest that the flow of albumin into the interstitial space could be of importance for the tissue penetration of highly protein bound antibiotics. The results also indicate dose-dependent pharmacokinetics for dicloxacillin.