The aim of this study was to retrospectively analyse the cost-effectiveness of different types of controlled ovarian hyperstimulation (COH) protocols and regimes used in in vitro fertilization procedures at a national level. Information was gathered from the National Centre for Assisted Reproduction (Bulgaria). Out of 2849 patients, 2757 were included in the study. The patients were treated with three main protocols: gonadotrophin-releasing hormone (GnRH)-antagonist protocol, GnRH-agonist protocol and COH protocols without GnRH-analogues. In all main COH protocols, different types of gonadotrophins were combined in seven therapeutic schemes. A decision tree model was built for the cost-effectiveness analysis. Each decision node representing the three main COH protocols included seven possible chance nodes representing the COH therapeutic regimens. The results were evaluated based on the number of live-born children. The mean cost differed statistically significant between the three main types of protocols (p D 0.0001) and between all seven COH regimens. In terms of live birth, the GnRH agonist protocols were more effective, followed by GnRH-antagonist protocols and those without GnRH-analogues. The decision tree model confirmed that considering the probability of the therapeutic regimens being prescribed, the GnRH-agonist protocol is the cost-effective one with the smallest cost per live-born child (5033, 51 BGN). The other two protocols could also be considered cost-effective because the incremental cost effectiveness ratio is very low and is below the gross domestic product per capita for 2015. The Governmental Authorities, considering also the cost-effectiveness criteria, should carefully revise the trend towards a wider use of GnRH-antagonist protocols.