Experienced entrepreneurs are typically considered to be wellsprings of both wealth creation and innovation. However, given that prior research has provided evidence of an inverse relationship between economic performance and innovation performance, innovation performance of experienced entrepreneurs requires greater scrutiny. In this study, we examine the question: under what conditions do serial entrepreneurs produce impactful innovations in their subsequent ventures? Using data on 334 VC-funded companies, our study suggests that the familiarity garnered by founders through their prior industry experience may limit the venture’s propensity to produce impactful innovation. Our findings contribute to the literature on serial entrepreneurship and innovation.