An influenza virus infection – “having the flu” – is very common in Europe, as each year an influenza epidemic goes around from November to April. While these infections are most often mild, the elderly and people with certain health conditions are at risk for serious complications and even death. Both the treatment of these complications (by the general practitioner and in hospitals) and the days that people who are sick stay home from work, cost a country’s economy money. Therefore, governments recommend yearly vaccination for these risk groups, to reduce both the health losses and economic costs of these influenza epidemics. Of course, organising this and vaccinating all those people, also costs the government money. This systematic review gives an overview the cost-effectiveness of the newest generation of vaccines, the quadrivalent influenza vaccines: making the balance between the costs and health benefits of vaccination programs with these vaccines, compared to the current situation. This study finds that introducing or extending quadrivalent influenza programs would both improve the overall health of the population and be cost-effective for society; it should therefore be considered for all groups described here. More research into the optimal form of this program is necessary before implementation. Why is this relevant? Governments routinely reimburse mass vaccination programs, to prevent influenza-related-illness and to minimise the economic costs of seasonal influenza pandemics. In these vaccination programs, there are two schools of thought. Countries like Belgium, France and Germany vaccinate mainly the people at risk for complications of infection, while for example the UK and the Baltic and Nordic states focus on children, who are the main transmitters of the virus. Implementation and reimbursement of these programs should be evidence-based, to avoid wasting taxpayer’s money and provide the most efficient health care. This systematic review investigates the cost-effectiveness of different vaccination program with quadrivalent influenza vaccines and finds that all these programs are cost-effective. The strategy of vaccinating children, should be explored by all countries, next to the existing programs for elderly and at-risk patients.