Differences between healthy subjects and associated disease risks are of substantial interest in clinical medicine. Based on clinical presentations, Traditional Chinese Medicine (TCM) classifies healthy people into nine constitutions: Balanced, Qi, Yang or Yin deficiency, Phlegm-dampness, Damp-heat, Blood stasis, Qi stagnation, and Inherited special constitutions. In particular, Yang and Yin deficiency constitutions exhibit cold and heat aversion, respectively. However, the intrinsic molecular characteristics of unbalanced phenotypes remain unclear. To determine whether gene expression-based clustering can recapitulate TCM-based classification, peripheral blood mononuclear cells (PBMCs) were collected from Chinese Han individuals with Yang/Yin deficiency (n = 12 each) and Balanced (n = 8) constitutions, and global gene expression profiles were determined using the Affymetrix HG-U133A Plus 2.0 array. Notably, we found that gene expression-based classifications reflected distinct TCM-based subtypes. Consistent with the clinical observation that subjects with Yang deficiency tend toward obesity, series-clustering analysis detected several key lipid metabolic genes (diacylglycerol acyltransferase (DGAT2), acyl-CoA synthetase (ACSL1), and ATP-binding cassette subfamily A member 1 (ABCA1)) to be down-and up-regulated in Yin and Yang deficiency constitutions, respectively. Our findings suggest that Yin/Yang deficiency and Balanced constitutions are unique entities in their mRNA expression profiles. Moreover, the distinct physical and clinical characteristics of each unbalanced constitution can be explained, in part, by specific gene expression signatures. Copyright (C) 2017, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.