The objective of this article is to assess the possibility of differences in factor substitution in the production of small and large U.S. manufacturing establishments. For empirical implementation, we specify and estimate separate three-factor translog production factors, using confidential plant-level data for five four-digit industries extracted from the U.S. Bureau of the Census Longitudinal Research Database. Our primary finding is that for most industries under study, small establishments appear to be at least as flexible as large establishments in factor substitution. This finding, together with our previous results on economies of scale (Nguyen and Reznek, 1991), suggests that for the five industries under examination, large size is not a necessary condition for efficient production.