The effect on serum lipoprotein concentrations of chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) was examined in eight normolipemic patients with radiolucent gallstones during constant liquid formula infusion into the duodenum. Every patient received each bile acid (1000 mg/day) during two consecutive randomized 4-week periods. During treatment with CDCA but not UDCA, the serum triglycerides decreased by an average of 26%. Mean HDL cholesterol decreased by 46% during CDCA therapy and remained unchanged during UDCA administration. Simultaneous measurements of biliary lipid secretion showed a significant negative correlation between HDL cholesterol concentration and hepatic secretion of CDCA (r = −0.652) and a positive correlation between the LDL cholesterol/HDL cholesterol ratio and hepatic secretion of CDCA (r = 0.840). Despite their close chemical relationships and similar effects on biliary lipids, CDCA and UDCA differ markedly in their effects on serum lipoproteins. Because of this and minor side effects, UDCA seems to be a safer agent than CDCA for cholesterol gallstone dissolution.