In this paper, we investigate the relationship between organizational culture (OC) profiles and the adoption of Industry 4.0 (I4.0) design principles. We surveyed 153 middle and senior managers from Brazil and India, whose manufacturing companies have been implementing I4.0. Participants provided answers regarding the perceived OC characteristics that prevail in their companies, which were assessed based on the Competing Values Framework. We also collected data on the adoption levels of I4.0 design principles, whose analysis was conducted through the utilization of multivariate data analysis techniques. Our results indicated that, depending on the I4.0 design principle, OC profiles (Clan, Adhocracy, Market and Hierarchy) may either corroborate or impair its adoption, allowing the verification of the hypothesized relationships. The understanding of the association between OC profiles and I4.0 design principles provides practitioners with arguments to identify possible problems during their digital transformation. As changes in OC require significant efforts and are usually time-consuming, companies that can anticipate those issues might face a smoother transition towards the Fourth Industrial Revolution, hence, obtaining competitive advantages.