Multivitamin/mineral supplements (MVMs) are widely used in many populations. MVMs, together with iron and folic acid, are recommended for pregnant women to improve birth outcome and to reduce low-birthweight and rates of miscarriage. However, MVM use is common in the general population as well. The aim of the present review was to evaluate the safety of long-term use of these supplements. To examine the safety of MVM use, we performed a literature search for randomized controlled studies involving supplementation 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 MVMs in pregnant women and healthy adults and six studies in the elderly where adverse effects were explicitly addressed. Only minor adverse events (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 effect of food and fortified food, and does not increase mortality. Taken together, these findings indicate that MVMs can be safe for long-term use (>10 y).