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This research explores the influence of entrepreneurial orientation (EO) on SMEs located at core and peripheral regions, by focusing on a single dimension of EO: proactiveness. We conducted a quantitative study of 626 Israeli SMEs. Business growth, as measured by the rate of change in number of employees, was found to be significantly higher in the core region. As expected, proactiveness was found to strongly affect SME growth as well as firm expansion to international markets. Our analysis shows that the difference in business growth between regions can be attributed also to a lower level of ownersʼ proactiveness in peripheral regions since it was found to mediate the effect of peripheral location on firm growth. Differences in proactiveness levels may be explained by the historical development of peripheral regions. Our results have useful implications for policies that aim to promote growth and development in peripheral regions.