Gaucher disease (GD) is frequently associated with reduced plasma levels of low density lipoproteins, presumably due to increased catabolism of LDL. The purpose of this study was to determine the distribution of Tc-99m LDL (Tc-LDL) in Gaucher patients, and compare the findings to bone marrow distribution. Four patients with non-neuropathic Gaucher disease (type 1) underwent baseline whole body imaging at 4 and 24 h after injection of dialyzed autologous LDL labeled with 10-20 mCi Tc-99m-pertechnetate. Three of the four patients were treated with macrophage-targeted alglucerase (Ceredase). The LDL studies were compared to concurrent bone marrow scans performed with 10 mCi Tc-99m sulfur colloid (Tc-SC). Follow-up Tc-LDL and Tc-SC scans were obtained 12-14 months later. Tc-LDL activity was abnormally increased in the spleen and long bones of the upper and lower extremities. Liver activity was also increased. Prominent blood pool activity 4 h after injection mostly cleared on the 24-hour images. The distribution of Tc-SC was congruent with Tc-LDL activity. All patients had mild-to-moderate hepatomegaly and peripheral bone marrow expansion. One patient had been previously splenectomized and the remaining three had moderate-to-severe splenomegaly. Two of the three treated patients showed regression of peripheral bone marrow activity with therapy, along with a comparable decrease in Tc-LDL uptake. Our study with Tc-LDL and Tc-SC suggests that in patients with Gaucher disease native LDL is taken up by the reticuloendothelial system (RES) of the spleen and bone marrow in addition to increased uptake by the liver. This abnormal uptake (presumably by macrophages of the RES) may account for accelerated LDL catabolism and reduced plasma levels of LDL. Serial LDL studies can be performed, allowing for longitudinal follow-up after drug or enzyme therapies.