Allostatic load (AL) is a theoretical framework that describes the cumulative physiologic effects of adaptation to change or stress throughout the lifespan. AL is operationalized by a composite index of multiple biomarkers. Accordingly, genes, behavior and environment contribute to AL. To determine if individual differences in AL may be influenced by inherent genetic variation, we calculated an allostatic load index (ALI) for 182 Caucasian subjects derived from a population-based study of chronic fatigue syndrome. Nearly 65% of the subjects in this study sample reported fatiguing illness. ALI was calculated based on 11 measures representing metabolic, cardiovascular, inflammatory, hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) activities. Subjects were dichotomized into high (ALI > or = 3) or low (ALI < 3) AL groups, and the association between high AL and 129 polymorphisms in 32 genes related to the HPA axis, neurotransmission, inflammation, cardiovascular and metabolic functions were evaluated. Polymorphisms in angiotensin-1 converting enzyme (ACE), corticotropin-releasing hormone receptor 1 (CRHR1), and serotonin receptors (HTR3A and HTR4) were associated with AL (p=0.0007-0.0486), but only one polymorphism, rs4968591, in ACE remained significant after correction for multiple comparisons. The T allele of ACE rs4968591 was more common in subjects with high AL (67.5%) than in subjects with low AL (49.3%) (p=0.0007), and this effect appeared independent of age, sex, body mass index and fatigue status. Additionally, high interleukin-6 (IL-6; p(trend)=0.04), and C-reactive protein (CRP; p(trend)=0.01) levels, as well as low urinary cortisol levels in females (p=0.03) were associated with the T allele, which may result in allele-specific binding of the transcription factor, E2F1. Our results suggest a role for ACE in the bidirectional communication between the central nervous and immune systems in response to stress. Further studies will be needed (a) to replicate the association between AL and ACE polymorphisms in population studies designed to differentiate the effects of sex, age and racial/ethnic background, (b) to evaluate the effect of allele-specific binding of E2F1 at rs4968591, and (c) to examine the role of ACE in the co-regulation of CRP, IL-6 and cortisol.