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Aim: To investigate the fatty acid-based functional lipidomics of patients on long-term home parenteral nutrition receiving different intravenous lipid emulsions., Methods: A cross-sectional comparative study was carried out on 3 groups of adults on home parenteral nutrition (HPN), receiving an HPN admixture containing an olive-soybean oil-based intravenous lipid emulsion (IVLE) (OO-IVLE; n = 15), a soybean- medium-chain triacylglycerol-olive-fish oil-based IVLE (SMOF-IVLE; n = 8) or HPN without IVLE (No-IVLE; n = 8) and 42 healthy controls (HCs). The inclusion criteria were: duration of HPN ≥ 3 mo, current HPN admixtures ≥ 2 mo and HPN infusions ≥ 2/wk. Blood samples were drawn 4-6 h after the discontinuation of the overnight HPN infusion. The functional lipidomics panel included: the red blood cell (RBC) fatty acid (FA) profile, molecular biomarkers [membrane fluidity: saturated/monounsaturated FA ratio = saturated fatty acid (SFA)/monounsaturated fatty acid (MUFA) index; inflammatory risk: n-6/n-3 polyunsaturated fatty acid (PUFA) ratio = n-6/n-3 index; cardiovascular risk: sum of n-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) = n-3 index; free radical stress: sum of FA trans isomers = %trans index] and FA pathway enzyme activity estimate (delta-9-desaturase = D9D; delta-6-desaturase = D6D; delta-5-desaturase = D5D; elongase = ELO). Statistics were carried out using nonparametric tests. The amount of each FA was calculated as a percentage of the total FA content (relative%)., Results: In the OO-IVLE group, the percentage of oleic acid in the RBCs was positively correlated with the weekly load of OO-IVLE ( r = 0.540, P = 0.043). In the SMOF-IVLE cohort, the RBC membrane EPA and DHA were positively correlated with the daily amount of SMOF-IVLE ( r = 0.751, P = 0.044) and the number of HPN infusions per week ( r = 0.753; P = 0.046), respectively. The SMOF-IVLE group showed the highest EPA and DHA and the lowest arachidonic acid percentages ( P < 0.001). The RBC membrane linoleic acid content was lower, and oleic and vaccenic acids were higher in all the HPN groups in comparison to the HCs. Vaccenic acid was positively correlated with the weekly HPN load of glucose in both the OO-IVLE ( r = 0.716; P = 0.007) and the SMOF-IVLE ( r = 0.732; P = 0.053) groups. The estimated activity of D9D was higher in all the HPN groups than in the HCs ( P < 0.001). The estimated activity of D5D was lower in the SMOF-IVLE group than in the HCs ( P = 0.013). The SFA/MUFA ratio was lower in all the HPN groups than in the HCs ( P < 0.001). The n-6/n-3 index was lower and the n-3 index was higher in the SMOF-IVLE group in comparison to the HCs and to the other HPN groups ( P < 0.001). The %trans index did not differ among the four groups., Conclusion: The FA profile of IVLEs significantly influenced the cell membrane functional lipidomics. The amount of glucose in the HPN may play a relevant role, mediated by the insulin regulation of the FA pathway enzyme activities., Competing Interests: Conflict-of-interest statement: Prof. Loris Pironi has been a consultant for Baxter SpA, Shire SpA and BBraun SpA; Prof. Carla Ferreri is a co- founder of Lipinutragen srl, originating as a spin-off company officially recognised by the National Council of Research, Italy. Lipinutragen srl is concerned with the applications of membrane lipidomics regarding molecular diagnostics and health care, and participated in the study by paying the salary of one employee involved in the analyses and data collection (Michele Melchiorre). This does not alter the authors’ adherence to all policies of the World Journal of Gastroenterology as to sharing data and materials, which are unrestricted. No other competing interests of any nature (financial, non-financial, professional or personal) exist. Lipinutragen srl provided support in the form of a salary for Michele Mechiorre who was involved in GC-analysis of the FAs profile of IVLEs and of the RBC membrane, and in data collection, but did not have any additional role in the study design, decision to publish, or writing of the manuscript.