The interstitial cells of Cajal (ICCs) are fundamental in the generation of gastric slow waves. The role of these cells in gastroparesis has not been established. We studied 14 gastroparetic patients (9 diabetic, 4 idiopathic, and 1 postsurgical) for whom standard medical therapy had failed and who had been treated with a gastric electrical stimulator for at least 3 months. All patients had a full-thickness antral gastric wall biopsy at the time of surgery. The biopsy samples were stained with c -kit and scored for the presence of ICCs. Baseline electrogastrogram recordings were obtained for 30 minutes in the fasting state and for 2 hours after a test meal. The patients assessed their total symptom score at baseline and at 3 months. Five patients had almost no ICCs and were compared with nine patients with 20% to normal cell numbers. Both groups did respond symptomatically to gastric electrical stimulation. However, patients with depleted ICCs had significantly more tachygastria and had significantly greater total symptom scores at baseline and after 3 months of gastric electrical stimulation. ICCs are absent in some patients (up to a third) with diabetic or idiopathic gastroparesis, and the absence of these cells is associated with abnormalities of gastric slow waves, worse symptoms, and less improvement with gastric electrical stimulation.