To evaluate the role of ESWL in vivo for the treatment of human gallstones positioned on the blast path, a canine model was developed to determine the efficacy of stone fragmentation and the subsequent histopathological injury that occurs as a result of this therapeutic technique. Twenty-four 16- to 20-kg mongrel dogs were divided into five groups: I: ESWL without stone, autopsy at 48 hr (N = 6); II: ESWL with stone (mean diameter 16.8 mm, range = 14-19 mm), autopsy at 48 hr (N = 10); III: ESWL without stone, autopsy at 41-46 days (N = 6); IV: ESWL without stone, autopsy immediately after ESWL (N = 1); V: No ESWL or stone, autopsy 2 hr after anesthesia induction (N = 1). A human gallstone (96% cholesterol) was inserted by cholecystotomy (N = 10) in Group II only. All groups (N = 24) had operative placement of a 6.5 Fr accordion catheter into the gallbladder for radiographic visualization. For each blast path treatment, 2000 discharges were delivered at 18-24 kV. Histopathologically, the Group V gallbladder served as a control. Groups I, II, and IV revealed mild subacute injury; dog gallbladders in Group III showed regression of these changes. Total surface area (TSA) of Group II stones increased from a pre-ESWL mean of 6.60 ± 0.0.84 cm2 to 53.84 ± 26.8 cm2 post ESWL (P < 0.001). Cumulative post-ESWL fragment sizes for particles in ≤2-, ≤3-, ≤5-, <10- and ≥10-mm categories represented 32.9, 41.6, 49.4, 74.3, and 100% of pretreatment stone weight, respectively. These data indicate that human gallstones can be fractured to a variable degree when treated on the ESWL blast path and that TSA increased significantly. Gallbladder histopathologic changes appear to be reversible by 41-46 days post-ESWL. © 1988.