An in vivo model of Pseudomonas aeruginosa sepsis was developed with normal and neutropenic guinea pigs injected intravenously with a strain of Pseudomonas demonstrated in vitro to be synergistically susceptible to ticarcillin and tobramycin. Therapy with ticarcillin, tobramycin, or a combination of the two starting 4 hr after intravenous injection of microorganisms was administered every 2 hr for periods up to 40 hr. Each therapy was associated with significant reductions in bacterial counts in blood, liver, spleen, and kidney compared with untreated animals. In no tissue in either normal or granulocytopenic animals did therapy with a combination of ticarcillin and tobramycin reduce bacterial counts significantly more effectively than did the better single antibiotic agent alone. These findings suggest that when ticarcillin and tobramycin are administered to animals at doses equivalent to therapeutic doses given in humans, a synergistic effect in reduction of bacterial counts in parenchymal organs and blood is not observed. These studies may help explain clinical reports in humans describing a lack of synergistic activity of combination antibiotic therapy in patients with Pseudomonas sepsis.