To test the hypothesis that high-dose vitamin D2 supplementation would result in a lower incidence of radiographically detectable bone disease, we randomly assigned 40 very low birth weight infants to a control group who received vitamin D2 in a dosage of 400 IU/day and 41 to an experimental group who received a dosage of 2000 IU/day. After 6 weeks, radiographs from all infants were scored blindly for degree of radiographic bone disease, and serum osteocalcin and 25-hydroxyvitamin D levels were measured. Mean vitamin D intake was 360 +/- 141 (SD) IU/day in the control group and 2170 +/- 144 (SD) IU/day in the experimental group. Median 6-week serum 25-hydroxyvitamin D levels were 24 ng/ml (range 3 to 60 ng/ml) in the control group and 68 ng/ml (range 9 to 150 ng/ml) in the experimental group (p less than 0.001). Overall, 20% of the infants had evidence of moderate radiographic bone disease and only 2% were severely affected. The radiographic bone score (median = 2.5) and serum osteocalcin concentration (mean = 21.7 +/- 8.7 ng/ml) in the control subjects did not differ significantly from those in the experimental group (median bone score = 2.0; mean osteocalcin level = 24.1 +/- 7.9 ng/ml). Although there may be a subset of very low birth weight infants who would benefit from high doses of vitamin D, we conclude that no generalized clinical improvement can be attributed to this regimen alone.