Skin testing with Mycobacterium avium sensitin (MAS) RS 10/2 and purified protein derivative (PPD) was conducted on patients with pulmonary disease due to M. avium complex (MAC) or Mycobacterium tuberculosis (MTB) and no known immunodeficiency. Reactions ≥5 mm to either MAS or PPD were present in 37 (84%) of 44 MAC patients and 28 (97%) of 29 MTB patients. MAC patients had a mean MAS reaction of 13.8 (±8.3) mm and a mean PPD reaction of 3.5 (±8.6) mm (P < .001). MTB patients had a mean MAS reaction of 17.9 (±9.4) mm and a mean PPD reaction of 22.9 (±11.4) mm (P < .001). MAS-dominant skin tests (MAS reaction ≥5 mm larger than PPD reaction) were present in 32 (73%) of 44 MAC patients and 1 (3%) of 29 MTB patients. MAS-dominant skin tests had a specificity of 97% for discriminating MAC disease from MTB disease.