To assess the role of crystal size in biologic responses, we quantitated red blood cell lysis and lung inflammation and fibrosis in the mouse using 4 α-quartz preparations with average diameters of 1, 5, 7.8, and 11.2 μM. When compared on the basis of identical crystal surface areas, the 1-µm fraction was more hemolytic than the other 3 fractions. The three larger fractions had equivalent membranolytic activities. After 6 weeks of postintratracheal instillation of the crystals into mice, the 1-µm-diameter crystal fraction increased wet lung weights by 1.25 X that of saline controls, while a 1.75 X increase was found for the three larger crystal fractions. A similar response was found when evaluating fibrosis development by determining lung hydroxyproline levels. Measurement of the percentage of the crystal dose remaining in the lungs revealed that the biologic differences observed were not due to a difference in the clearance of the smaller crystal fraction. Thus, larger crystals of α-quartz produce a greater degree of inflammation and fibrosis when instilled into the lung than those of 1 4mUm diameter, even though the smaller crystals are more membranolytic in vitro and appear to be cleared from the lung at the same rate as the larger crystals.