Granulocyte-macrophage colony-stimulating factor (GM-CSF), a glycoprotein with hormonal properties, is produced by several cell types, most of which exist outside the CNS. GM-CSF, however, affects the CNS. If capable of crossing from blood to CNS, GM-CSF might be an important signalling molecule between the CNS and periphery. We used an established in vivo method in mice and rats to study passage of radioactively labelled GM-CSF from blood to CNS. We found that GM-CSF crossed the blood-brain barrier and blood-spinal cord barrier significantly faster than the control substance, albumin. Labelled GM-CSF was recovered in intact form by high performance liquid chromatography from brain after peripheral injection, and passage was not significantly reduced by simultaneous injection of unlabelled L-tryptophan. Both findings indicate that the observed passage of radioactivity was intact protein. Capillary depletion experiments showed that most of the GM-CSF was deposited in brain parenchyma rather than cerebral capillary endothelium. Co-injection of unlabelled GM-CSF significantly reduced the passage rate of labelled cytokine across the blood-brain and blood-spinal cord barriers, demonstrating that passage was mediated by a saturable system. In summary, a saturable mechanism transports GM-CSF intact from blood to CNS.