Cefotiam hexetil is a pro-drug of cefotiam available for oral administration. To evaluate cefotiam concentrations at the active site in skin and soft-tissue infections, drug levels in skin suction blister fluid (SBF), cantharides blister fluid (CBF) and serum were determined. Six healthy subjects received oral cefotiam 400 mg as cefotiam hexetil. On an other day 200 mg was injected intravenously. Following the oral dose, the bioavailability of cefotiam was 45.5%, and the maximum concentration in serum of 2.6 mg.l-1 was obtained at 2.1 h. Peak concentrations in both types of blister fluid (0.9 mg.l-1) were significantly lower than after the iv dose (SBF 1.4 mg.l-1, CBF 1.5 mg.l-1), and the peak levels occurred later (3.3 versus 1.5 h in CBF). Despite the delay, the extent of penetration was about 100% following either mode of administration (SBF, iv dose 112%, oral dose 117%). The cefotiam level in skin blister fluids declined significantly more slowly than the serum level. Following the oral dose, the mean terminal half life was serum 0.8 h, SBF 2.6 h and CBF 4.6 h. Cefotiam concentrations in the blister fluids were close to the MIC90 of Staphylococcus aureus, S. epidermis and H. influenzae and exceeded the MIC90 of Streptococci, E. coli and Proteus mirabilis. Thus, the oral administration of cefotiam 400 mg t.i.d. should be curative in the majority of bacterial infections of the skin and soft-tissues.