The systemic effects of endotoxicosis were evaluated in terms of cyclic nucleotide levels within left ventricular and gastrocnemius tissue. Endotoxicosis was induced in mice by repeated intraperitoneal injection of Escherichia coli endotoxin on days 1, 7, and 14. Tissues were harvested at the end of 1 and 2 weeks of endotoxicosis. Levels of cAMP and cGMP were monitored by 125I-radioimmunoassay. There was a significant total body weight loss associated with markedly decreased cAMP levels in both ventricular (P less than 0.025) and gastrocnemius (P less than 0.025) muscle. The cGMP levels were unchanged in the ventricular muscle. When relationships between the cyclic nucleotides and total body weight loss were examined, differences were obtained between cAMP and cGMP. There was a direct correlation between increase in cGMP in the ventricular muscle and weight loss and an indirect correlation between decreased cAMP levels and weight loss. These relationships show that the respective role of each nucleotide was similar in each of the tissues. Furthermore, when the data were evaluated through multiple linear regression analysis, improved correlation coefficients were obtained. These analyses confirm that several independent factors contribute to the change in cyclic nucleotide metabolism in differing muscle types as a result of endotoxin infection.