Background: Large animal models of myocardial infarction (MI) are essential for the development of novel therapeutic strategies. However, it is unclear which experimental factors are independent determinants of disease progression outcomes and the fidelity with which these models resemble MI in humans. The aim of this study was to investigate systematically what independently influences the outcome after MI in large animal models and determine which methodological factors influence primary endpoints and disease progression. Methods: We used control animal data from two meta-analyses of large animal models of MI. We performed univariable and multivariable meta-regression to analyze if potential relevant variables were influencing outcomes; infarct size as a ratio of the area at risk (IS/AAR), as a ratio of the left ventricle (IS/LV) and ejection fraction (EF). Pre-defined independent variables were species, sex, weight, ischemia model (open vs closed), occlusion type (temporary vs permanent), occluded vessel, follow-up duration, use of co-medication, use of immunosuppression and study quality. Outcomes and variables were complemented per dataset if needed. Results: Our analyses yielded 246 relevant studies, reporting 1500, 1221 and 775 control animals for IS/AAR, IS/LV and EF respectively. Multivariable meta-regression showed IS/AAR was influenced by species (p<0.001), sex (p=0.03), co-medication (p=0.01), occlusion type (p<0.001), occluded vessel (p=0.002) and follow-up (p=0.001). For IS/LV occlusion type (p=0.03), occluded vessel (p=0.03) and study quality (p=0.03) showed significant effects. EF measurements revealed that species (p=0.04), sex (p=0.04) and occluded vessel (p=0.05) were independent predictors. Using these variables, we can partially predict these outcomes for certain study setups. Conclusion: Many methodological variations exist in the design of large animal MI studies. This should be taken into account when selecting a model to study therapy efficacy. We provide evidence that disease manifestation and progression greatly depend on certain biological characteristics, e.g. location of MI and sex of the patient. It is therefore possible that therapies have a different effect in specific patient populations.