Plasma lipidome is now increasingly recognized as potentially important marker of chronic diseases but the exact extent of its contribution to the inter-individual phenotypic variability in family studies is unknown. Here, we used the rich data from the ongoing San Antonio Family Heart Study (SAFHS) and developed a novel statistical approach to quantify the independent and additive value of the plasma lipidome in explaining metabolic syndrome variability in Mexican American families recruited in the SAFHS. Our analytical approach included two pre-processing steps - principal components analysis of the high resolution plasma lipidomics data and construction of a subject-subject lipidomic similarity matrix. We then used the Sequential Oligogenic Linkage Analysis Routines (SOLAR) software to model the complex family relationships, lipidomic similarities and other important covariates in a variance components framework. Our results suggested that even after accounting for the shared genetic influences, indicators of lipemic status (total serum cholesterol, triglycerides and high-density lipoprotein cholesterol) and obesity the plasma lipidome independently explained 22% variability in the homeostatic model of assessment - insulin resistance (HOMA-IR) trait and 16% - 22% variability in glucose, insulin and waist circumference. Our results demonstrate that plasma lipidomic studies can additively contribute to an understanding of the inter-individual variability in metabolic syndrome.