Four of five patients with brain metastases from melanoma had increased lofetamine I 123 uptake in the region of the tumor deposits. A comparison group of five patients with melanoma with no clinical or radiologic evidence of brain involvement and 46 of 47 patients without malignant melanoma but with known brain tumors of other histologic types had normal or decreased iofetamine I 123 brain uptake in the region of the tumor. An exception was one patient whose metastatic small cell lung cancer to the brain showed focally increased uptake. These findings suggest that certain brain tumors such as melanoma are capable of selectively binding iofetamine I 123 because of specific chemical properties of the radiopharmaceutical. Increased uptake of iofetamine I 123 in brain lesions in a patient at risk for metastatic melanoma may be a useful aid to differential diagnosis.