Restless legs syndrome is a neurological disorder characterized by unpleasant sensations and pain, predominantly in the lower extremities while at rest, accompanied by an uncontrollable urge for movement for relief. We report on two affected male individuals, a father and son, ages 71 and 47, from a family in which three generations carry the diagnosis. To evaluate any potential benefit of D-ribose in this condition, each individual orally consumed 5-g doses of D-ribose daily at different trial stages. Each stage lasted 3 weeks with a 2-week washout period between stages. The initial stage involved a single 5 gm dose of D-ribose consumed at breakfast. Throughout the second stage, D-ribose was taken at breakfast and lunch. In the third stage, D-ribose was taken at all meals, breakfast, lunch, and dinner. Diaries by the subjects pertaining to their documentation and severity of restless legs syndrome symptoms was compiled. During the initial stage both men reported a general feeling of more energy and less fatigue, most notably after exercise, without any significant changes in their symptoms. With the increase in the daily dose of D-ribose, in the second stage, their leg twitching and the feeling to move during the day was reduced for 1 subject, and rarely present in the other. Both still experienced the unpleasant sensations during the night. However, during the final stage, a further increase in the daily dose of D-ribose eliminated their daily symptoms and the symptoms at night were of a lesser degree and had a later occurrence. Both men reported that D-ribose did not totally eliminate their discomfort, but the severity and onset of symptoms affecting their quality of life was substantially improved with D-ribose without any adverse reactions.