Potential inappropriate prescriptions (PIPs) in elderly population are a source of additional clinical and economic burden on healthcare systems. PIPs can derive from inappropriate dosage or duration of treatment, off-label use, use in contraindicated circumstance and in particular drug-drug interactions (DDIs). PIPs are associated with an increased risk of drug–related adverse events, especially in the elderly population, including hospitalization and mortality. Furthermore, older patients are more at risk for PIPs because they are often treated with complex drug regimens. The age-related changes in drug pharmacokinetics and pharmacodynamics can raise the risk of PIPs. Polypharmacy is common in the elderly population, with more than 60% receiving a simultaneous prescription of five drugs or more. There is a strong relationship between the number of dispensed drugs and the probability of potential DDIs. The use of administrative databases signifies a significant step forward, representing a valuable tool to estimate the prevalence of clinically relevant potential DDIs as well as to examine possible predictors of potential DDI exposure. The results show that the elderly population has a high risk of DDIs, also highlighting a very high rate of suboptimal drug prescribing in the elderly. As physicians still have some difficulty in managing this problem, the urgent implementation of national educational programs is essential, in order to highlight factors that raise the risk of DDIs and to increase an appropriate use of drugs.