Controversy exists in the literature regarding the efficacy of bone health-related nutrients, especially calcium and vitamin D, in preventing fractures. The aim of our present study was to determine the effect of multivitamin and mineral supplementation on fracture incidence among 3,318 participants from a nutritional intervention trial in Linxian, China. A total of 1,461 men and 1,857 women were enrolled and randomized to daily supplementation with 26 vitamins and minerals tablet or placebo pills for 6 years, followed by a 16-year post-interventional follow-up. The dates, sites, and causes of the fractures were collected retrospectively via a standardized questionnaire. Cox proportional hazard model was used to estimate hazard ratios and 95% confidence intervals of fracture incidence in the intervention versus the placebo group. A total of 221 fractures (57 in men and 164 in women) occurred during the entire study period of 21 years and 9 months. In men, the supplement reduced the risk of fracture by 63% during the trial period, and this protective effect was sustained and statistically significant when analysis included both the trial period and 5- or 10-year post-intervention follow-up (years 0-11, P = 0.04; years 0-16, P = 0.02, respectively). The protection against fracture was not apparent >10 years after cessation of the intervention. In women, no significant effect of supplementation on fracture incidence was seen in any of the study periods. These results demonstrate that a 6-year multivitamin and mineral intervention was associated with significant reduction of fracture risk and fracture-related hospitalization in men, but not in women.