The well documented increased susceptibility of the asplenic host to overwhelming sepsis by encapsulated organisms has led to three popular prophylactic measures in patients: 1) pneumococcal vaccination; 2) vaccination with oral penicillin prophylaxis; or 3) vaccination with penicillin use at the first sign of infection. An animal model (weanling CD-1 rats) was utilized to evaluate these prophylactic measures. One hundred sixty rats underwent splenectomy and were divided into four treatment groups: I) sham vaccination; II) pneumococcal vaccination; III) vaccination and IM penicillin 24 hours after intraperitoneal inoculation of 106Streptococcus pneumoniae type III; IV) vaccination and IM penicillin starting 3 days before IP inoculation. Six days following the bacterial challenge survival rates by group were: I) 5%; II) 25%; III) 100%; IV) 100% (p< 0.001 by x2likelihood ratio). Mantel- Cox log rank analysis of survival curves yielded significant differences between all groups except HI and IV (p< 0.001). This study in weanling rats supports the use of penicillin in the asplenic host. Daily prophyactic penicillin or penicillin started at the first sign of infection appears to be equally effective. Randomized studies in humans would determine the best regimen.