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Background: Many foals that develop thoracic ultrasonographic lesions as a result of Rhodococcus equi infection heal on their own. However, most of these foals receive antimicrobials because foals at risk of developing clinical pneumonia cannot be identified. Untargeted lipidomics is useful to identify candidate biomarkers. Objectives: (a) To describe the changes that occur in foal lipidomics as a result of ageing (birth to 8 weeks) and (b) To compare these results with those observed in foals after experimental infection with R. equi. Study design: Experimental study. Methods: Healthy newborn foals (n = 9) were challenged with R. equi intratracheally the first week of life. Foals were treated with antimicrobials if they developed clinical pneumonia (n = 4, "clinical group") or were closely monitored if they showed no signs of disease (n = 5 "subclinical group"). An unchallenged group (n = 4) was also included. All foals were free of disease (transtracheal wash fluid evaluation and culture as well as thoracic ultrasonography) by 8 weeks of life. Plasma lipidomics was determined by LC‐MS weekly for the study duration (8 weeks). Results: Both ageing and experimental infection altered the foal's plasma lipidome as demonstrated by multivariate statistical analysis. The intensities of 31 lipids were altered by ageing and 12 by infection (P <.05). Furthermore, nine lipids changed by more than twofold between clinical and subclinical groups. Main limitations: The number of foals is limited. Foals were experimentally challenged with R. equi. Conclusions: Ageing and R. equi infection induced changes in the plasma lipidome of foals. These experimental results provide the background for future work in the discovery of earlier biomarkers of R. equi pneumonia. Early identification of foals at risk of developing clinical pneumonia is key in order to decrease antimicrobial use and development of antimicrobial resistance. [ABSTRACT FROM AUTHOR]