Fosfomycin inhibits bacterial cell wall synthesis at the initial stage. It can act synergistically with beta-lactams. The effect of the combination of fosfomycin and selected penicillins and cephalosporins against staphylococci, Pseudomonas aeruginosa, Pseudomonas cepacia and selected Gram-negative bacteria was determined. Synergy was determined by agar dilution and checkerboard titration methods; synergy was defined as an FIC index less than or equal to 0.5 and partial synergy greater than 0.5 to 0.75. Concentrations of drugs used were those that would be reached in man by intravenous and oral routes. Fosfomycin combined with nafcillin and with cefotaxime against staphylococci showed synergy for most isolates. For methicillin-resistant Staphylococcus aureus, synergy or partial synergy was found for 90% of isolates. Synergy was less frequently found with Staphylococcus epidermidis. The MICs for S. aureus were reduced from greater than or equal to 32 micrograms/ml to less than or equal to 1 microgram/ml. Fosfomycin was synergistic with ticarcillin, piperacillin, azlocillin, ceftazidime, aztreonam and imipenem against 31 to 61% of P. aeruginosa. MICs were reduced from greater than or equal to 128 micrograms/ml to 8-32 micrograms/ml, depending upon the agent. Although fosfomycin acted synergistically with azlocillin, piperacillin and ceftazidime against some P. cepacia, most often there was an indifferent interaction and MICs were in the resistant range, greater than or equal to 128 micrograms/ml. The interaction of fosfomycin and ampicillin was synergistic against a number of strains of Enterobacteriaceae, Proteus vulgaris and Providencia rettgeri, yielding MICs in an achievable range. The combination of fosfomycin with beta-lactams may be clinically useful in selected situations, particularly for methicillin-resistant staphylococci and beta-lactam-resistant P. aeruginosa.