Radical innovation in professional settings faces an institutional challenge. Professionals enjoy autonomy predicated on jurisdictional knowledge and can resist radical innovation if their interests are threatened. Our study examines if and how managers mediate professional resistance and ensure that radical innovation can take hold. A comparative case study of 12 Italian hospitals introducing integrated service configurations shows that managers may hold back from introducing radical innovation where they judge professional resistance as insurmountable. Executives reinforce, rather than challenge, the status quo, and discourage middle managers from further actions. Where the professional context is more receptive because of micro‐institutional affordances, then, managers enact different tactics. Managers may centralize decision‐making through political work, which, however, increases professional resistance and hinders radical innovation. Managers may adopt project management approaches, which facilitate local experiments, but struggle to scale‐up the radical innovation. Most successful cases are characterized by executive and middle managers enacting a two‐step institutional work, which reconfigures the regulative, normative, and cognitive foundations of professional boundaries and practice. The comparative study shows how managers can support radical innovation in collaboration with professionals. In the two‐step institutional work, executive and middle managers develop stable alliances with local professional groups to provide cognitive/normative foundations of radical innovation; second, they allow professionals to inhabit nascent institutional arrangements to make sense of how these fit with their prevailing interests, norms, and beliefs; third, they co‐develop new structures/rules that encourage professionals to pursue radical innovation; finally, they perform maintenance work to preserve professionals' attachment to new institutions.