PurposeThe upper tolerable intake level for vitamin D in the general population has been set at 4000 international units (IU) daily, but considerable uncertainty remains. We summarized reported harmful effects of a daily vitamin D supplement of 3200–4000 IU in trials lasting ≥ 6 months.MethodsWe performed a systematic review and meta-analysis of randomized controlled trials in several databases and identified 22 trials reporting safety data. Parameters of calcium metabolism, falls, hospitalization, and mortality were assessed.ResultsThe selected trials comprised a total number of 12,952 participants. All trials used supplemental vitamin D3. The relative risk (RR) of hypercalcemia in the vitamin D vs. control arm was 2.21 (95%CI: 1.26–3.87; 10 studies), with a vitamin D-induced frequency of hypercalcemia of 4 cases per 1000 individuals. Subgroup analysis in trials with > 100 and ≤ 100 study participants revealed an RR of 2.63 (95%CI: 1.30–5.30; 7 studies) and 0.80 (95%CI: 0.24–2.62; 3 studies), respectively (Pinteraction= 0.06). Risks of falls and hospitalization were also significantly increased in the vitamin D arm with an RR of 1.25 (95%CI: 1.01–1.55; 4 studies) and 1.16 (95%CI: 1.01–1.33; 7 studies), respectively. Risks of hypercalciuria, kidney stones, and mortality did not differ significantly between study arms. Quality assessment revealed high risk of incomplete reporting of safety-related outcome data.ConclusionSupplemental vitamin D doses of 3200–4000 IU/d appear to increase the risk of hypercalcemia and some other adverse events in a small proportion of individuals, indicating that this dose is not completely safe. In future studies, rigorous reporting of safety-related outcomes is needed when using moderately high doses of vitamin D.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00394-023-03124-w.