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Background: Integrating patient preferences in Health Technology Assessment (HTA) is argued to improve uptake, adherence, and patient satisfaction. However, how to elicit and incorporate these preferences in HTA in a systematic and scientifically valid manner is subject to debate. Objective: This article provides a systematic review of the challenges to integrating patient preferences in HTA that have been raised in the literature about patient preferences in HTA. Methods: A systematic review of articles published between 2013 and 2017 addressing challenges to the integration of patient preferences in HTA was conducted in 7 databases. All issues with respect to the integration of patient preferences in HTA were extracted and divided into 5 categories: conceptual, normative, procedural, methodological, and practical issues. The issues were ranked according to how often they were mentioned. Results: Of 2147 retrieved articles, 67 were included in the analysis. Thirty-seven unique research issues were identified. In the majority of the articles, methodological issues were posed (82%), followed by procedural (73%), normative (51%), practical (24%), and conceptual (9%) issues. Frequently posed methodological issues concerned preference heterogeneity and choice of method. Common procedural issues concerned how to evaluate the impact of preference studies and their degree of being evidence based. Conclusions: This article provides an overview of issues with respect to the integration of patient preferences in HTA procedures. Most issues were of a methodological or procedural nature; yet, the large number of different issues points to the overall importance of further researching the different aspects concerned with patient preferences in HTA. Through its ranking of how many articles mention particular issues, this article proposes an implicit research agenda.