Background: Studies using Taiwan's National Health Insurance (NHI) claims data have expanded rapidly both in quantity and quality during the first decade following the first study published in 2000. However, some of these studies were criticized for being merely data-dredging studies rather than hypothesis-driven. In addition, the use of claims data without the explicit authorization from individual patients has incurred litigation. Objective: This study aimed to investigate whether the research output during the second decade after the release of the NHI claims database continues growing, to explore how the emergence of open access mega journals (OAMJs) and lawsuit against the use of this database affect the research topics and publication volume and to discuss the underlying reasons. Methods: PubMed was used to locate publications based on NHI claims data between 1996 and 2017. Concept extraction using MetaMap was employed to mine research topics from article titles. Research trends were analyzed from various aspects, including publication amount, journals, research topics and types, and cooperation between authors. Results: A total of 4473 articles were identified. A rapid growth in publications was witnessed from 2000 to 2015, followed by a plateau. Diabetes, stroke, and dementia were the top 3 most popular research topics whereas statin therapy, metformin, and Chinese herbal medicine were the most investigated interventions. Approximately one-third of the articles were published in open access journals. Studies with two or more medical conditions, but without any intervention, were the most common study type. Studies of this type tended to be contributed by prolific authors and published in OAMJs. Conclusions: The growth in publication volume during the second decade after the release of the NHI claims database was different from that during the first decade. OAMJs appeared to provide fertile soil for the rapid growth of research based on NHI claims data, in particular for those studies with two or medical conditions in the article title. A halt in the growth of publication volume was observed after the use of NHI claims data for research purposes had been restricted in response to legal controversy. More efforts are needed to improve the impact of knowledge gained from NHI claims data on medical decisions and policy making.