Restless Legs Syndrome (RLS) is characterized by bothersome leg discomfort accompanied by an urge to move to obtain relief and symptoms are worse at night and on lying down. There is at least partial and temporary relief with activity. It is also an opioid responsive disorder, often accompanied by iron deficiency with or without anemia, and inflammation may be a precipitating factor in some cases. We created two in-vivo opiate receptor knock out mouse models of RLS – a triple opiate receptor knock-out mouse and a mu opiate receptor knock-out mouse. Both sets of animals were restless during the sleep period as is also true of RLS. Both of our knockout models showed statistically significantly decreased Hemoglobin and Hematocrit indicating anemia and both models showed statistically significant decreases in serum iron suggestive of either iron deficiency anemia or inflammatory anemia. The rest of the hematologic studies were not consistent enough to determine which of these two types of anemia was present in either model. An additional experiment in normal wild type mice showed a statistically significant decrease in serum iron when an opiate receptor blocker was used. To our knowledge this is the first demonstration that deficiency of endogenous opioids might play a role in the production of anemia. Our hypothesis is that an intact endogenous opiate system is necessary for red cell homeostasis. The presence of opioid receptors both on red blood cells and on various immunologically based white blood cells suggest mechanisms by which deficiency in the endogenous opiate system could cause anemia of either the iron deficiency or inflammatory types. The administration of opioid agonists or antagonists to iron deficient cultures of red blood cell precursors is a next step in determining the role of the endogenous opiate system in the maintenance of red cell homeostasis and in the possible prevention of iron deficiency or inflammatory anemia where iron dysregulation is key.