The etiology of the tall stature almost invariably seen in homocystinuric patients is not known. The effect of metabolic control and the role of the GH-IGF system on growth were investigated in IO patients with homocystinuria. There was a direct correlation between the plasma free homocyst(e)ine and growth velocity SD scores in 18 patient years (r, 0.46; p < 0.05). Plasma 2-y cumulative free homocyst(e)ine and height SD scores were directly correlated (r, 0.82; p < 0.01). Growth velocity SD scores were Lower in patients with optimal metabolic control than in those with poorer control (-0.10 +/- 0.65 versus 0.95 +/- 0.68, p < 0.01). Height SD scores were also lower in the optimally controlled group (-0.01 +/- 0.81 versus 1.73 +/- 0.88, p < 0.05). GH and GH-related peptides did not deviate significantly from the reference ranges. These findings suggest that overgrowth is directly mediated by homocysteine, that the GH-IGF axis is not involved, and that it may be prevented by optimal metabolic control.