Zymosan, a yeast cell wall preparation from Saccharomyces cerevisiae, stimulates the reticuloendothelial system (RES) in animals. Pretreatment with zymosan induces resistance to several types of shock. We have shown evidence that zymosan given intraperitoneally (IP) induces greater protection than intravenous (IV) zymosan against E coli peritonitis in the rat. Moreover, IP zymosan has few systemic RES effects, which are commonly associated with IV zymosan. IV and IP zymosan stimulation were compared for effectiveness against experimental fibrinopurulent peritonitis in dogs (a peritonitis model quite similar to clinical peritonitis). Ten dogs received zymosan IV (10 mg/kg), ten dogs received zymosan IP (10 mg/kg), and eight dogs received an equal volume of saline IP on three consecutive days. On day 4, a 7.5 cm length of terminal ileum was isolated and its blood supply ligated to create an infarcted, blind loop of bowel. This loop was left in the peritoneal cavity for five days. Five-day survival was 80% (8/10) for the zymosan IP (P less than 0.05), 60% (6/10) for the zymosan IV and 12.5% (1/8) for the saline controls. All survivors were sacrificed at five days and found to have an intact enteric anastomosis with varying degrees of walled-off abscess at the site of the necrotic loop. Histologic evaluation of intraabdominal organs, peritoneum, and abscess wall was carried out. The IP zymosan had no significant systemic RES effects, whereas the IV zymosan produced a marked increase in liver and spleen weights. These findings reinforce the hypothesis that local nonspecific RES stimulation could have a major role in the preparation of certain high-risk patients for abdominal surgery where the chance of peritoneal soilage is high.