The antibacterial action of amphipathic derivatives of isoniazid (INH) as compared to the parent hydrophilic molecule was determined against the bacteria of the Mycobacterium avium complex (MAC) using a 7H11 agar-dilution method. The results obtained showed a higher activity of 1-isonicotinyl-2-palmitoyl hydrazine and 1-isonicotinyl-2-(12 hydroxy dodecanoyl) hydrazine as compared to INH. However, when one mannose residue was terminally attached to the fatty acid chain of the latter, it lost its anti-MAC activity. 1-isonicotinyl-2-D-galacturonic acid hydrazone (but not hydrazine) also showed increased activity against MAC. Although pristinamycin was shown to bind to M. avium surface lipids, the INH-pristinamycin derivative was not more active than INH alone. These findings are discussed in respect to a proposed mechanism of diffusion across a lipid barrier.