Updates of resuscitation guidelines have limited high-level supporting evidence. Moreover, the overall effect of such bundled practice changes depends not only on the impact of the individual interventions but also on their interplay and swift functioning of the entire chain of survival. Therefore, real-world data monitoring is essential. We performed a meta-analysis of comparative studies on outcomes before and after successive guideline updates. On January 16, 2019, we searched for comparative studies (PubMed, Web-of-Science, Embase, and the Cochrane Libraries) reporting outcomes before and after resuscitation guidelines 2005, 2010, and 2015. We followed PRISMA, Cochrane, and Moose-recommendations. Studies on outcomes during the 2005 versus 2000 guideline period (n = 23; 40,859 patients) reported significantly higher ROSC (odds ratio [OR] 1.21 [1.04 to 1.42], p = 0.014), survival to admission (OR 1.34 [1.09 to 1.65], p = 0.005), survival to discharge (OR 1.46 [1.25 to 1.70], p <0.001), and favorable neurologic outcome (OR 1.35 [1.01 to 1.81], p = 0.040). Studies on outcomes during the 2010 versus 2005 guideline period (n = 11; 1,048,112 patients) indicated no difference in ROSC (OR 1.25 [95% confidence interval 0.95 to 1.63], p = 0.11), whereas survival to discharge improved significantly (OR 1.30 [1.17 to 1.45], p <0.001). Only 2 studies reported on neurologic outcomes, both showing improved outcome after the 2010 guideline update. No data on the 2015 guidelines were available. This meta-analysis on real-world data of >1 million patients demonstrates improved outcomes after the 2005 and 2010 resuscitation guideline updates, and a lack of data on the 2015 guideline. In conclusion, although limited in terms of causality, this study suggests that the sum of all efforts to improve outcomes, including updated CPR guidelines, contributed to increased survival after cardiac arrest.