Objective: Guidelines on the need for dose adaptation of vitamin D3 supplementation according to baseline serum 25(OH)D are inconclusive. The effects of increasing doses of vitamin D3 at lower baseline serum 25(OH)D values on the serum 25(OH)D after 4.2 and 11 months were determined in an observational study. Design: A prospective observational study. Methods: Out of 1481 consecutive women and men with a recent clinical fracture, 707 had a baseline 25(OH)D level !50 nmol/l and were supplemented with increasing doses of vitamin D3 (400, 800, 1700, and R3500 IU/day) according to the lower baseline 25(OH)D. Final analysis was restricted to the 221 participants who had full follow-up data available for 11 months. Results: Serum 25(OH)D R50 nmol/l was achieved in 57-76% of patients after 4.2 months and in 73-79% after 11 months. These percentages were similar for all doses (PZ0.06 and PZ0.91 respectively). The mean achieved 25(OH)D was similar for all dose groups (56.1-64.0 nmol/l after 4.2 months and 60.2-76.3 nmol/l after 11 months). With multivariate analysis, the increase in 25(OH)D (17G32.0 after 4.2 months and 24.3G34.0 nmol/l after 11 months) was dependent on the baseline 25(OH)D (P!0.001), not on supplementation dose, season, age, BMI, or gender. Conclusions: The increase in serum 25(OH)D was significantly larger with higher vitamin D3 supplementation doses. However, this dose-effect response was mainly explained by the baseline 25(OH)D, not the supplementation dose, with a greater magnitude of response at lower baseline 25(OH)D concentrations. In 21-27% of patients, serum 25(OH)D3 levels did not reach 50 nmol/l after 11 months, at any dose. Further studies are needed to identify possible causes of suboptimal response such as non-compliance, undiagnosed malabsorption syndromes, or variability in cholecalciferol content of the vitamin D supplements.