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Background Medical quality registers are useful sources of knowledge about diseases and the health services. However, there are challenges in obtaining valid and reliable data. This study aims to assess the reliability in a national medical quality register. Methods We randomly selected 111 patients having had a stroke in 2012. An experienced stroke nurse completed the Norwegian Stroke Register paper forms for all 111 patients by review of the medical records. We then extracted all registered data on the same patients from the Norwegian Stroke Register and calculated Cohen’s kappa and Gwet’s AC1 with 95 % confidence intervals for 51 nominal variables and Cohen’s quadratic weighted kappa and Gwet’s AC2 for three ordinal variables. For two time variables, we calculated the Intraclass Correlation Coefficient. Results Substantial to excellent reliability (kappa > 0.60/AC1 > 0.80) was observed for most variables related to past medical history, functional status, stroke subtype and discharge destination. Although excellent reliability was observed for time of stroke onset (ICC 0.93), this variable was hampered with a substantial amount of missing values. Some variables related to treatment and examinations in hospital displayed low levels of agreement. This applies to heart rate monitoring (kappa 0.17/AC1 0.46), swallowing test performed (kappa 0.19/AC1 0.27) and mobilized out of bed within 24 h after admission (kappa 0.04/AC1 −0.11). Conclusion A majority of the variables in The Norwegian Stroke Register have substantial to excellent reliability. The problem areas seem to be the lack of completeness in the time variable indicating stroke onset and poor reliability in some variables concerning examinations and treatment received in hospital. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.