Twenty patients who suffered persistent intractable pain from a variety of disorders underwent medial thalamotomy with the Leksell Gamma Knife. The lesions were directed at the intralaminar nuclei, the lateral portion of the medial dorsal nucleus, the centromedian and the parafascicular nuclei. Lesions were made with radiation doses from 140 to 180 Gy using a 4-mm beam collimator helmet and either a single isocenter (1 patient), two isocenters (17 patients) or three isocenters (2 patients). Two thirds of the patients experienced either excellent or good pain relief in a follow-up period between 1 and 22 months. One patient showed temporary complications which resolved, and 2 other patients also suffered complications which currently are improving. One patient died due to radiation necrosis following a bilateral thalamotomy. Gamma Knife thalamotomy may offer a potentially safe and effective alternative for the treatment of certain difficult persistent pain problems.