Primary fibromyalgia (FM) is a common clinical condition affecting mainly middle-aged women. Of the etiologies previously proposed, chronic hypoxia seems the one best supported by recent biochemical and histological findings. We postulate that FM symptoms are predominantly caused by enhanced gluconeogenesis with breakdown of muscle proteins, resulting from a deficiency of oxygen and other substances needed for ATP synthesis. We present data supporting a critical role for magnesium and malate in ATP production under aerobic and hypoxic conditions; and indirect evidence for magnesium and malate deficiency in FM. After treating 15 FM patients for an average of 8 weeks with an oral dosage form with dosages of 1200-2400 mg of malate and 300-600 mg of magnesium, the tender point index (TPI) scores (X +/- SE) were 19.6 +/- 2.1 prior to treatment and 8 +/- 1.1 and 6.5 +/- 0.74, respectively, after an average of 4 and 8 weeks on the magnesium malate combination (p < 0.001). Subjective improvement of myalgia occurred within 48 h of supplementation. In six FM patients, following 8 weeks of treatment, the mean TPI was 6.8 +/- 0.75. After 2 weeks on placebo tablets, the TPI values increased to a mean +/- SE of 21.5 +/- 1.4 (p < 0.001). Again, subjective worsening of muscle pain occurs within 48 h of placebo administration. A double-blind placebo control trial is currently underway.