To further our understanding of the mechanisms by which ethambutol potentiates the effect of other antimycobacterial drugs on mycobacteria we have studied the initial physico-chemical interaction between ethambutol and the Mycobacterium avium cell envelope using batch reaction microcalorimetry. When strains of M. avium were exposed to ethambutol an immediate endothermic reaction was recorded. When the M. avium cells were pre-treated with ethambutol this strongly affected the initial interaction between streptomycin and the bacterial cell surface. When the M. avium cells were simultaneously exposed to a combination of ethambutol and streptomycin an altered initial interaction with streptomycin was seen. These data suggest that ethambutol may potentiate the effect of other antibacterial drugs on M. avium by increasing cell wall permeability.