Chronic Fatigue Syndrome (CFS) is an illness that has been estimated to affect 800,000 people in the United States. Up to 80% of those affected are women. These individuals suffer from severe fatigue that impairs daily activity, diminishes quality of life for years and has no known cure. CFS represents an economic burden for society and its healthcare institutions. Hypothetical initiating events for CFS include infections, psychiatric trauma and exposure to toxins. An emerging body of evidence demonstrates alterations in the immune system. Immunologic impairment may lead to episodic activation of latent viruses -held in check in healthy individuals by cytotoxic lymphocytes. Current treatments for the syndrome are symptom-focused and relatively ineffective. Improved treatment options will come with a better understanding of the underlying pathophysiology of the syndrome. Our goal is to improve the understanding of CFS pathophysiology and to develop biomarkers useful in diagnosis, in defining subsets and in therapeutic trials. The rationale for the proposed research is based on our work and that of others that suggests immune dysfunction in CFS. In this study, we will use a longitudinal study design that incorporates, within an 18-month window, two random time points and two time points corresponding to the patient perception of times of relative intensification and relative amelioration of CFS related symptoms. We have two Specific Aims. Specific Aim 1 will determine the extent to which patients, or subset of patients who meet the CFS case definition have immune impairment, or patterns of immune dysfunction, as compared to healthy, sedentary controls. Specific Aim 1 will determine the relationship of immune markers related to lymphocyte cytotoxic function, lymphocyte activation and inflammation to symptom severity over the 18 months of observation. Specific Aim 2 will define the molecular biology of impaired immune function in CFS on samples collected at the four time points and allow us to determine if changes in disease severity correlate with changes in the lytic pathway of cellular immunity. By defining immune function at the molecular level, we will identify potential biomarkers and targets for intervention with immuno-modulatory therapies and the means to measure the efficacy of these therapies.