Background <p>A key underlying principle of causal inference is that of well-defined interventions. Although ultra-processed food (UPF) has been associated with a greater risk of type 2 diabetes (T2D), subtypes of UPFs may exert different strengths and directions of associations. The main objective of this study was to systematically evaluate the current literature on subtypes of UPFs and their associations with T2D and to contextualize these findings within the framework of sufficiently well-defined interventions for causal inference.</p> Methods <p>We searched PubMed and Embase for relevant articles. Cohort studies of adult men and women without T2D were included. Two independent researchers screened the articles and evaluated risk of bias using the ROBINS-E tool. UPFs were categorized into eight subtypes. A post-hoc analysis of 52,201participants in the Danish Diet, Cancer and Health (DCH) cohort was performed to illustrate the implications of vaguely defined interventions. We formed a fictive food group (the terrible five) combining foods that have been associated with T2D: sugar sweetened beverages, processed meat, red meat, refined grains and vegetables, and investigated the associations with T2D.</p> Results <p>Out of 222 articles screened for eligibility, 6 cohort studies with 635,332 participants (average follow-up of 6-26.1 years) were included. Most studies on UPF ready-to-eat-dishes; meat-based products; and artificially and sugar-sweetened beverages were positively associated with T2D whereas UPF dairy products; and sweets, snacks and confectionaries were generally inversely associated with T2D, although with some variation. Overall risk of bias was considered moderate to high in all included studies. In the DCH cohort, a positive association between the “terrible five” and T2D was observed. Intake of vegetables was inversely associated with T2D.</p> Conclusions <p>The systematic review showed different strengths and directions of associations on the risk of T2D across the different subtypes of UPFs. Aggregating these sources into a coarse food category such as UPF may therefore undermine the core principle of well-defined interventions and, as illustrated in our post-hoc analysis, can mask individual associations. This study illustrates potential unintended consequences of broad food categorizations such as UPFs and hamper implementation of UPF policies without further improvement of the definition or mechanistic understanding.</p> Trial Registration <p>The protocol was registered in PROSPERO (ID: CRD420251058458).</p>