Our pilot studies (PSs) show that chronic fatigue (CF) is a problem in the general population and is associated with higher adrenergic neurovascular tone (ANVT). ANVT is measured by systolic time intervals (STI = PEP/LVET × 100%). Baseline (low stress level) ANVT is predicted by temperance analysis testing (r = .98, p < .01). ANVT can be increased by pain, stress, certain foods, and sympathomimetic drugs, which were avoided during the study. In our prospective studies, as with PSs, a random sample of the general population was acquired using patients with a normal distribution of STI values (25-56%). Patients were 3/1 women/men, age range 30 to 65 years. Exclusions were patients with elevated C-reactive protein, HbA1c > 6.0, depression, fibromyalgia, and smokers. PS criterion of STI at 25 to 36% was used to identify CF patients with significantly higher symptom levels (SL = 1-100 scale of fatigue scored by patient) versus normal age-matched controls (C). Blind correlations were made by serial measurements of systolic blood pressure (SBP), SL, cardiac output (CO), and systemic vascular resistance (SVR) by two-dimensional echocardiography. This was done at baseline (time 1 = T1, without significant external stress) and during treatment (Rx) (T2). T2 was 1 year for group (G)1 and G2 and at 6 months for G3. All data were placed into a blind matrix for later analysis. Patients were grouped by STI ranges (G1 25-30%, G2 31-36%, G3 a random sample of patients 25-36%, and C 50-56%) using PS guidelines. Rx of G1 and G2 CF patients consisted of amitriptyline (10-50 mg/d) and diltiazem CD (240-360 mg/d) and 500 mg calcium/d. G3 patients received 1,500 mg of calcium/d without other medications. Prospective results: Group means are shown. See Table. Where * = significantly different from C at p < .01 by t-test. ** = Significant (**sig) change from T1 to T2 at p < .01 by t-test. CF was found in 28% of the random sample of the general population. G1, G2, and G3 had significantly lower STI and CO with significantly higher SL at T1 versus C. Rx significantly reduced SL and SVR and increased STI and CO in G1 and G2. G3 patients had sig** increase in SL with conventional calcium therapy. This was associated with sig** increases in SVR, with sig** decreases in STI and SBP. G3 patients had sig** increases in CF and classic symptoms of fibromyalgia according to the criteria of the American College of Rheumatology. These studies show the importance of measurement of CO and SVR in addition to BP measurement using the standard formula for SVR. CF occurs in the general population owing to higher ANVT without inflammatory disorders. Thus, reduction in ANVT and increased CO significantly reduces SL in CF.