ObjectiveThe aim was to compare multimorbidity patterns identified with the two most commonly used methods: hierarchical cluster analysis (HCA) and exploratory factor analysis (EFA) in a large primary care database. Specific objectives were: (1) to determine whether choice of method affects the composition of these patterns and (2) to consider the potential application of each method in the clinical setting.DesignCross-sectional study. Diagnoses were based on the 263 corresponding blocks of the International Classification of Diseases version 10. Multimorbidity patterns were identified using HCA and EFA. Analysis was stratified by sex, and results compared for each method.Setting and participantsElectronic health records for 408 994 patients with multimorbidity aged 45–64 years in 274 primary health care teams from 2010 in Catalonia, Spain.ResultsHCA identified 53 clusters for women, with just 12 clusters including at least 2 diagnoses, and 15 clusters for men, all of them including at least two diagnoses. EFA showed 9 factors for women and 10 factors for men. We observed differences by sex and method of analysis, although some patterns were consistent. Three combinations of diseases were observed consistently across sex groups and across both methods: hypertension and obesity, spondylopathies and deforming dorsopathies, and dermatitis eczema and mycosis.ConclusionsThis study showed that multimorbidity patterns vary depending on the method of analysis used (HCA vs EFA) and provided new evidence about the known limitations of attempts to compare multimorbidity patterns in real-world data studies. We found that EFA was useful in describing comorbidity relationships and HCA could be useful for in-depth study of multimorbidity. Our results suggest possible applications for each of these methods in clinical and research settings, and add information about some aspects that must be considered in standardisation of future studies: spectrum of diseases, data usage and methods of analysis.