The aim of this study is to investigate the prevalence of potential drug-drug interactions (PDDIs), as well as classifying them in relation to level of severity, scientific evidence, time of onset, and potential clinical impact in adult and older adult patients with diabetes mellitus 2 (DM2). This cross-sectional study was conducted in a tertiary care outpatient center. The consecutive sample was made up of 140 patients with DM2. The Anatomical-Therapeutic-Chemical Classification was used for classifying the classes of medications. The PDDIs were analyzed using the DRUG-REAX® system. The relationships between PDDI and the associated factors were ascertained using a multiple logistic regression model. The prevalence of total PDDI was 75 %, and the prevalence of major severity PDDI was 20.7 %. Simvastatin (30.8 %), captopril/enalapril (12.8 %), and oral anti-diabetics/insulin (12.8 %) were the medications which were most involved in the major PDDI, bringing relevant potential clinical impacts such as rhabdomyolysis, hyperkalemia, and important glycemic alterations. Polypharmacy was associated with PDDI (adjusted odds ratio = 10.46, 95 % confidence interval = 4.10–26.71). Diabetics were highly exposed to clinically significant PDDI. It is important that health professionals should be aware of the risks related to PDDI, so that measures may be implemented in order to assure safe care for the patient.