ScopeMetabolomics approach is focused on identifying all metabolites present in a biological sample (metabolome). Consumption of cocoa products has been related to health benefits including positive effect on cardiovascular health.Methods and resultsTwenty volunteers were included in this randomized, crossover, and controlled clinical trial. After a 2‐wk washout period, subjects received 40 g/day of cocoa powder with 500 mL skimmed milk (cocoa with skimmed milk intervention) or 500 mL/day of skimmed milk (skimmed milk intervention) for 4‐wk. Urine (24 h) samples were collected at baseline and after each intervention and were analyzed by HPLC‐hybrid quadrupole TOF in negative and positive ionization modes followed by multivariate analysis. This analysis revealed a marked separation between the cocoa with skimmed milk intervention and skimmed milk intervention and baseline periods. Thirty‐nine compounds linked with cocoa intake, including alkaloid metabolites, polyphenol host and gut microbial metabolites (hydroxyphenylvalerolactones and hydroxyphenylvaleric acids), diketopiperazines and N‐phenylpropenoyl‐l‐amino acids were identified. In the case of endogenous metabolites, putative identifications suggested that metabolites linked with carnitine metabolism and sulfation of tyrosine were decreased by the consumption of cocoa.ConclusionLC‐MS metabolomics strategy allows the defining of a complex metabolic profile derived from cocoa phytochemicals. Likewise, the identification of endogenous markers could lead to new hypotheses to unravel the relationship between cocoa intake and cardiovascular diseases.