A series of 143 salicylanilides substituted in positions 4 and 5 and in positions 3' and 4' was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. To describe the structure-antimycobacterial activity relationships (QSARs), an approach based on the combination of the Free-Wilson and Hansch methods was employed (the substituent constants were used in the case of the substituents on the phenyl ring; indicator parameters were used for the substituents on the acyl moiety). The relationships between the antimycobacterial activity and physico-chemical parameters of all substituents were also explored. The quadratic representation of lipophilicity parameters did not lead to significant correlations.