We sought to determine if patients with cystic fibrosis and sputum cultures positive for Mycobacterium avium complex (MAC) have delayed-type hypersensitivity to an M. avium sensitin. Seventeen (33%) of 51 selected patients had MAC isolated from at least one sputum culture. Skin tests with purified protein derivative and M. avium sensitin demonstrated that five (10%) of 51 patients were anergic, and anergy was correlated with use of systemic steroids. Sixteen (35%) of 46 nonanergic patients had M. avium-dominant skin test reactions. Twelve (75%) of these 16 patients with cultures positive for MAC had M. avium-dominant skin tests; the specificity of skin testing was 87%. These data suggest that most patients with cystic fibrosis and sputum cultures positive for MAC have infection rather than colonization with MAC. Skin testing with M. avium sensitin is a sensitive and specific method for screening these infections.