The title of an article is the main entrance for reading the full article. The aim of our work therefore is to examine differences of title content and form between original research articles and its changes over time. Using PubMed we examined title properties of 500 randomly chosen original research articles published in the general major medical journals BMJ, JAMA, Lancet, NEJM and PLOS Medicine between 2011 and 2020. Articles were manually evaluated with two independent raters. To analyze differences between journals and changes over time, we performed random effect meta-analyses and logistic regression models. Mentioning of results, providing any quantitative or semi-quantitative information, using a declarative title, a dash or a question mark were rarely used in the title in all considered journals. The use of a subtitle, methods-related items, such as mentioning of methods, clinical context or treatment increased over time (all p < 0.05), while the use of phrasal tiles decreased over time (p = 0.044). Not a single NEJM title contained a study name, while the Lancet had the highest usage of it (45%). The use of study names increased over time (per year odds ratio: 1.13 (95% CI: [1.03‒1.24]), p = 0.008). Investigating title content and form was time-consuming because some criteria could only be adequately evaluated by hand. Title content changed over time and differed substantially between the five major medical journals. Authors are advised to carefully study titles of journal articles in their target journal prior to manuscript submission.