Antiphospholipid syndrome (APS) is an autoimmune thrombophilia diagnosed by established clinical and serological criteria, distinguishing it from other causes of venous thromboembolism (VTE). This study investigated whether VTE is associated with plasma lipidome changes and whether an APS-specific lipid signature can be identified. We performed quantitative mass spectrometry-based lipidomics on plasma from healthy controls (n = 16), patients having VTE without APS (n = 16) and triple-positive APS patients (n = 17), profiling 224 lipid species across all major classes. Ceramide species (Cer 18:1;O2/16:0,/18:0,/20:0 and/26:0) and the Cer 18:0/Cer 24:0 ratio were elevated in both VTE groups relative to healthy controls, consistent with a shared thrombotic state. To identify APS-specific changes, LASSO logistic regression defined a minimal discriminating lipid panel. PE 40:5 (elevated 1.69-fold in APS), SM 43:2;O2 and PC O-34:2 (both reduced by 21%–24%) were combined into a parameter-free composite score that discriminated APS from VTE without APS with an AUC of 0.857. PE 40:5 has previously been associated with cardiovascular inflammatory activation, whilst reduction of PC O-34:2 may reflect increased conversion to platelet-activating factor and/or plasmalogen consumption under the pro-inflammatory conditions of APS. The co-occurrence of elevated ceramides and decreased SM 43:2;O2 in APS raises the hypothesis of enhanced acid sphingomyelinase activity driving sphingomyelin-to-ceramide conversion. Prospective validation in larger cohorts is warranted to assess its utility as a complement to serological APS diagnostics. In conclusion, despite the limited sample size, plasma lipidomics identifies a three-lipid composite score that discriminates APS from VTE without APS.