To simulate the weightless condition, eight rhesus monkeys, instrumented with solid-state pressure transducers, were horizontally restrained in body casts for 28 d. Blood volume decreased an average of 13% after 14 d of restraint, due mainly to a drop in plasma volume. Aortic pressure and heart rate responses to norepinephrine and phenylephrine decreased after 14 d of restraint. The monkeys did not show a statistically significant decreased tolerance to a 90 degree sudden upright tilt after horizontal restraint. During the fifth week of casting, four animals were subjected to +Gz acceleration tests on a centrifuge. The acceleration tolerance of the casted monkeys was significantly reduced compared to four similarly instrumented control animals. These findings indicate that the cardiovascular deconditioning associated with simulated weightlessness results from an inability to maintain central blood volume during orthostatic stress.