The aim of the present study is twofold: to establish the response of hepatic machinery of plasma protein biosynthesis to cholera intoxication, and to examine the same response of alloxan‐diabetic hepatocytes with minimal capacity of synthesis of plasma proteins. Direct lesion of hepatic plasma membranes via ip administration of cholera toxin to male rats resulted in a typical acute‐phase response (APR) of plasma proteins, which had regressed to levels similar to those of healthy controls approximately at 240 h postintoxication. The d 2 response to a single 0.16 mg/kg body weight dose was typified by a 23% reduction in the level of albumin, but a 6‐ and 24‐fold increase in the levels of fibrinogen and alpha‐1‐acid glycoproteins, respectively. This response was similar (in direction but not in magnitude) to the acute‐phase reaction to a simple subcutaneous administration of cartageenan. The intoxication was accompanied by a massive leakage, into the peritoneal cavity, of plasma fluid, which embraced the complete profile of acute‐phase reactants. A three‐step mechanism is proposed to account for the observations as follows: (1) There is a rapid formation of a stable complex between subunit B of the toxin and ganglioside GM1 of hepatic plasma membrane. An APR is induced in response to the alteration(s) of hepatic plasma membranes. (2) The release, from the choleragen‐membrane complex, of polypeptide A1 and its subsequent penetration of the hepatic membrane result in both activation of adenylate cyclase and increased vascular permeability of hepatic membranes. This leads, in turn, to exudation of components of plasma fluid in the peritoneal cavity of intoxicated rats. An alternate rationale for this exudation is the slow leakage of plasma proteins out of the blood vascular system (possibly through microvesicles) into the peritoneal cavity of cholera intoxicated rats. The spectrum of acute‐phase hepatic secretory components was mirrored in the corresponding peritoneal exudate. (3) The increased hepatic membrane flow provides the continued renewal of plasma membrane proteins required for its eventual repair by either endocytosis or sloughing off the toxin‐bound membrane segments into the circulatory system, thus producing regression of APR.