What challenges do researchers face when leading transdisciplinary integration? We address this question by analyzing transdisciplinary integration within four thematic synthesis processes of the Swiss National Research Programme (NRP 61) on Sustainable Water Management. We adapt an existing analytical framework to compare transdisciplinary integration across the four synthesis processes regarding different types of generated knowledge (systems, target and transformation knowledge), different types of involved actors (core team, steering committee, advisory board, scientific experts and practice experts) and different levels of actor involvement (information, consultation and collaboration) at different stages of the processes. Based on a structured ex-post self-evaluation of the four synthesis processes, we present core challenges of transdisciplinary integration as perceived by core team members of the four synthesis processes and formulate empirically derived recommendations for designing and implementing future processes. We suggest that future synthesis processes should be conceptualized and initiated concurrently with all other individual research projects, involving a phasing-in stage where leaders conceptualize transdisciplinary integration, an intermediate stage of intense knowledge integration involving all relevant actor groups in a functional and dynamic way, and a final phasing out stage, where synthesis results are consolidated within the research program, validated by different actor groups and diffused to the target audiences. We argue that transdisciplinary integration requires professional competences, management skills and enough time. Finally, we suggest fostering communities of practice (CoP) to link committed leaders and enable mutual learning processes beyond the boundaries of individual synthesis projects or research programs.