The role of endogenously released cholecystokinin (CCK) in mediating gallblader (GB) contraction was evaluated in 12 normal volunteers and 24 patients with gallstones (11 additional gallstone patients were excluded because of failure of adequate ultrasonographic visualization). CCK concentrations before and after oral administration of fat (Lipomul®) were measured by a specific radioimmunoassay. CCK release was correlated with changes in GB volume determined simultaneously by ultrasonography. On the basis of gallbladder contraction and operative findings, gallstone patients were divided into “contractors”(14),“noncontractors”(6), and “hydrops”(4). Lipomul caused prompt release of CCK in normal volunteers and all groups of gallstone patients. The changes (basal to peak) in plasma CCK (pg/ml) for the different groups were as follows: normal volunteers (108±9 to 200±16), contractors (77±10 to 128±13), noncontractors (59±7 to 159±38), and hydrops (43±5 to 113±47). The total integrated output of CCK (0-60 min) was greater in normal volunteers (3975±762 pg-min/ml) than in contractors (1530±567 pg-min/ml). Lipomul caused similar GB contraction in normal volunteers and contractors (from basal volumes to maximal contraction); these changes were from 19.5±2.3 ml to 5.6±1.0 ml in normal volunteers, and from 19.6±3.2 to 5.2±1.0 in contractors. Plasma concentrations of CCK and GB volume were highly correlated in the 12 normal volunteers (r=-0.89, p< 0.01) and in the 14 contractors (r=-0.99, p< 0.01)), but the GB was significantly (p< 0.01) more sensitive to changes in plasma CCK in the gallstone contractors than in the normal volunteers. The authors suggest that there may be two groups of gallstone patients, noncontractors and contractors. Stasis may be important in the pathogenesis of gallstones in the noncontractors, whereas in contractors, the authors speculate that an abnormality in the CCK-gallbladder relationship (characterized by diminished CCK release and increased GB sensitivity to CCK) may be involved in the evolution of the disease.