Multivitamin/mineral supplements (MVM) are widely used in many populations. In particular, in pregnant women, MVM together with iron and folic acid are recommended to improve birth outcome and reduce low birth weight and rates of miscarriage. However, MVM use is common in the general population. This raises questions regarding the safety of long-term use of these supplements. To estimate the safety of MVM use, we performed a literature search for randomized, controlled studies for supplements with a combination of at least nine vitamins and three minerals at a maximum concentration of 100% of the recommended dietary allowance. We found nine studies evaluating the use and efficacy of MVM in pregnant women and healthy adults and six studies in the elderly where adverse effects were explicitly addressed. Only minor adverse effects (e.g., unspecific gastrointestinal symptoms) were reported in all studies. In particular, there were no significant differences between treatment and placebo groups. MVM use within the range of the dietary reference intake will not result in excess intake, even when including the impact of food and fortified food, and does not increase mortality. Taken together, these findings indicate that MVM can be safe for long-term use (more than 10 y).