Abstract Previous studies have demonstrated that shortterm administration of recombinant human macrophage colony- stimulating factor (rhM-CSF) reduces plasma cholesterol in rabbits, nonhuman primates, and human subjects. This study extended the dose schedule of rhM-CSF to 8 weeks of continuous intravenous infusion (CIVI) in the Watanabe heritable hyperlipidemic (WHHL) rabbit and expanded the scope to include an assessment of macrophage-derivcd foam cell development. Ten male WHHL rabbits were injected subcutaneously with 1% carrageenan to promote formation of a macrophage-rich foam cell granuloma.Rabbits were infused with either vehicle or rhM-CSF at 100 μg/kg per day (weeks 1 through 5) followed by 300 /μg/kg per day (weeks 6 through 8). rhM-CSF (100 fig/kg per day) decreased total plasma cholesterol by 45% at 2 weeks compared with controls. The gradual return of plasma cholesterol toward control concentrations over the subsequent 3 weeks correlated with the appearance of circulating antibodies specific to rhM-CSF. Granuloma weights at harvest (8 weeks after infusion) were significantly lower (2.8±0.7 g, mean±SEM) in rhM-CSF-treated rabbits relative to controls (7.1±1.5 g, p<.05). Granulomas from rabbits treated with rhM-CSF contained lower concentrations of cholesterol (2.0+0.7 versus 6.1 ±1.5 fig/mg, F<.03) and cholesteryl ester (0.7±0.4 versus 3.9±1.2 figlmg, p<.03) than controls. Histological evaluation revealed that granulomas from the rhM-CSF-treated rabbits were more fibrous and contained fewer foam cells than those from controls. Immunohistochemical localization of endogenous macrophage colony- stimulating factor (M-CSF) in granuloma tissue from vehicle- treated rabbits revealed a diffuse, faint staining pattern. Granuloma tissue from rhM-CSF-treated rabbits exhibited staining for M-CSF that was more intense than in tissue from control rabbits. This study showed that the CIVI of rhM-CSF produced a significant reduction in plasma cholesterol and granuloma foam cell formation in WHHL rabbits. The increase in immunoreactive M-CSF in granulomas from rhMCSF- treated rabbits suggested that M-CSF may have enhanced the viability of macrophages and modulated their function in a manner that stimulated the processing of cholesterol and its mobilization from the granuloma.