In an effort to optimize rational chemotherapy against M. avium infections in a clinically meaningful context, we tested whether liposome-encapsulated amikacin would effectively reduce the bacterial load in (i) intravenously infected immunodeficient SCID mice, (ii) immunocompetent mice in both early and late stages of intravenous infection, and (iii) immunocompetent mice with pulmonary M. avium infection. Although complete eradication of M. avium was never achieved following intravenous infection, mycobacterial CFUs decreased by 3 to 4 logs in the spleens and livers of mice treated for three weeks with twice-weekly intravenous injections of liposomal amikacin and continued to stay low in the liver, even in the absence of specific immunity. Mice treated in the chronic stage of infection equally benefited from therapy and showed signs of attenuated granulomatous inflammation in the liver. Even moribund mice responded to liposomal amikacin by significantly gaining weight and survived their infected untreated littermates by at least 4 months. In contrast, during pulmonary M. avium infection, treatment with liposome-encapsulated amikacin only resulted in a transient plateau of bacterial proliferation in the lungs, and the infection exacerbated immediately after cessation of therapy.