Considerable inter-individual variability has been reported in the biochemical and physiological responses to long-chain omega-3 (LC omega-3) supplementation, yet the origins of this variability remain poorly understood. Postprandial studies provide an opportunity to examine differences in intestinal handling of dietary lipids and may offer insights into the mechanisms underlying heterogeneous responses to supplementation. A literature review identified postprandial studies reporting plasma or whole-blood LC omega-3 responses following supplementation with different lipid formulations. Studies were included when variability could be expressed as the coefficient of variation (CV) for the area under the concentration-time curve (AUC or iAUC). Variability was examined according to dose, lipid formulation and study laboratory to identify potential sources of inter-individual variation. Twenty-one studies comprising 36 treatment arms met the inclusion criteria. Supplements included triacylglycerols, phospholipids, monoacylglycerols, free fatty acids, ethyl esters, emulsified ethyl esters and whole-food sources of LC omega-3 fatty acids. Marked inter-individual variability was observed irrespective of lipid formulation, with more than 64% of treatment arms exhibiting CV values exceeding 50%. Variability was unrelated to LC omega-3 dose (r² = 0.002, p > 0.05). Comparison of paired treatments performed within individual laboratories suggested that analytical methods and laboratory-specific factors accounted for little of the observed variation, with only 28% of the variance explained and fewer than half of paired comparisons within laboratories differing by less than 10% in CV. Similarly, no significant difference in variability was observed between formulations requiring intestinal lipolysis (triacylglycerols/phospholipids) and pre-digested formulations (monoacylglycerols/free fatty acids), suggesting that digestive hydrolysis alone is unlikely to explain the large differences in postprandial responses. Gastrointestinal (GI) symptoms were reported in three of the studies, suggesting possible malabsorption of LC omega-3 fatty acids. The persistence of substantial variability across lipid formulations suggests that biological differences in intestinal lipid absorption, intracellular fatty acid trafficking, re-esterification, chylomicron assembly and secretion are likely contributors. Genetic polymorphisms affecting proteins involved in these pathways, together with differences in enterocyte lipid partitioning associated with obesity and metabolic status, represent plausible mechanisms underlying heterogeneous postprandial LC omega-3 responses. We propose that inter-individual differences in intestinal processing of LC omega-3 fatty acids contribute to variable postprandial responses and may ultimately influence the incorporation of EPA and DHA into plasma and erythrocyte lipids during supplementation. If confirmed, this hypothesis has important implications for interpreting erythrocyte omega-3 status, designing clinical trials, and developing personalised approaches to LC omega-3 supplementation.