Background <p>Older patients often suffer from multiple disorders and are hence frequently burdened by polypharmacy. Prevention of cardiovascular events using antiplatelet drugs might be indicated among older populations, but there are no studies assessing platelet function in these patients.</p> Methods <p>Using impedance aggregometry, we compared platelet reactivity to 7 aggregation inducers between a group of 44 polymorbid older patients aged 78 + years (PP), and 50 generally healthy younger controls (median age, 44&#xa0;years). None of the subjects were treated with antiplatelet therapy. We also examined their response to antiplatelet drugs (acetylsalicylic acid, ticagrelor, vorapaxar) and an experimental compound, 4-methylcatechol, a small polyphenol metabolite of many natural polyphenolic compounds. Data analysis was performed in the whole group as well as after removing or splitting the groups based on concomitantly administered drugs. Linear mixed-effects modelling was used to investigate the impact of both drugs and comorbidities on the obtained results.</p> Results <p>A clinically achievable concentration of ASA (30&#xa0;µM) failed to block platelet aggregation when arachidonic acid was used as an inducer, but the response to ticagrelor, vorapaxar, and 4-methylcatechol with relevant inducers was significant. However, the sensitivity to ticagrelor and vorapaxar was lower in PP when compared to healthy controls. The analysis also confirmed similar activity for 4-methylcatechol, but lower activity for acetylsalicylic acid in our PP. Further analyses excluding specific drugs did not significantly alter these outcomes. Inflammatory markers and the presence of type 2 diabetes mellitus were significant predictors of platelet reactivity while basic blood parameter data had no clear impact.</p> Conclusions <p>The <i>ex vivo</i> response of platelets from PP to the standard antiplatelet drugs was lower. In contrast, they responded well to 4-methylcatechol.</p>