Sympathetic nervous system response to volume stress is more marked in patients with frequent hemodialysis-associated skeletal muscle cramps than in most patients who cramp infrequently. Accordingly, we conducted a double-blind, randomized, and balanced trial in which five patients with frequent hemodialysis-associated cramps were given either placebo or a prazosin dose (ranging from 0.25 to 1.0 mg) at the start of 16 dialysis sessions. These low doses of prazosin appeared to reduce cramp frequency in four of the five patients, and patient-stratified multiple logistic regression analysis indicated an aggregate 58% reduction in cramp frequency (p = 0.030). On the other hand, prazosin therapy was associated with an increased incidence of hypotension that required therapeutic intervention both during (p = 0.033) and after (p = 0.010) hemodialysis. Our findings support the hypothesis that sympathetic activation plays a pathogenetic role in hemodialysis-associated skeletal muscle cramps and suggest that pharmacologic attenuation of this response may be of therapeutic benefit.