Chronic hypothyroidism can result in an increased susceptibility to severe pulmonary or genitourinary tract infections. We postulate that decreased lysosomal activity in the pulmonary alveolar macrophage (PAM), peritoneal macrophage, and mononuclear leukocyte may be a factor which results in the impaired response to infections in hypothyrosis. In this study rats underwent total thyroidectomy and had their PAMs, peritoneal macrophages, and mononuclear leukocytes analyzed after 4, 8, and 12 weeks. The total lysosomal activity (postnuclear homogenate + lysosomal-rich cell fraction) of PAMs was 50% of age-matched controls. Peritoneal macrophage lysosomal enzyme activity was 25–30% of control activity. In separate experiments, rats were administered physiologic replacement of triiodothyronine (T 3) 8 weeks after thyroidectomy. This resulted in PAM and peritoneal macrophage lysosomal enzyme activity similar to control activity. Mononuclear leukocyte lysosomal enzyme activity from hypothyroid rats showed decreases in only one of the three enzymes monitored (β-glucuronidase). Hypothyroidism did result in a decrease in total number of mononuclear leukocytes harvested per animal. Administration of T 3 resulted in mononuclear leukocyte β-glucuronidase activity similar to euthyroid rats (44 ± 8 U/mg protein vs 42 ± 3 U/mg protein). In summary, hypothyroidism in the rat results in decreases in subcellular lysosomal enzyme activity in PAMs, peritoneal macrophages, and mononuclear leukocytes.