Introduction Elderly patients are particularly susceptible to polypharmacy issues because of age-related changes in pharmacokinetics and pharmacodynamics as well as to chronic diseases resulting in a continuous increasing demand for drugs. Objective This study captures the prevalence of polypharmacy and adherence in Greece and identifies related risk factors in adult patients with diabetes. Design A cross-sectional study was conducted among patients diagnosed with diabetes mellitus attending public and private outpatients' clinics in the regions of Attica and Western Greece. Results A total of 644 outpatients filled out the questionnaire (relative risk = 91.7%). As far as the medications were concerned, 47.8% of patients had been receiving antidiabetic medication monotherapy, 38.2% combination therapy with two antidiabetic drugs, 11.8% with three drugs, and 2.2% with four drugs. The vast majority of diabetic patients adhered to their medication regimen, and fewer adhered to their physician's diet and physical activity recommendations. Statistically significant differences were found between age group and the existence of polypharmacy (P = 0.005). Additionally, 44.4% of patients with comorbidities exhibited polypharmacy, compared with 4.8% of patients who were diagnosed only with diabetes (P = 0.001). Conclusion The development of new strategies and health policies is necessary for polypharmacy and adherence among diabetic patients to be limited.