Therapeutic plasma exchange (TPE) is used for a wide range of indications and is associated with well-described adverse events. However, no study has specifically focused on tolerance in elderly patients, despite its expected increasing use in this population. We conducted a single-center retrospective case-control study of all patients aged ≥ 75 years who underwent TPE between 2011 and 2023. Adverse events were identified through standardized surveillance forms completed contemporaneously. The primary outcome was the rate of any adverse event occurring during TPE sessions, compared between patients aged ≥ 75 years (elderly group) and those < 75 years. Elderly patients accounted for 7.4% of all TPE sessions during the study period. Thirty-one patients were included in each group, corresponding to 506 TPE sessions. Hypertension and cardiac disease were significantly more frequent in the elderly group. Overall adverse event rates were similar in the two groups (40.6% in < 75 years vs. 43.4% in ≥ 75 years, p = 0.592). Asymptomatic hypocalcemia was more frequent in elderly patients, whereas allergic reactions were more frequent in younger patients. One-year survival did not differ between groups (p = 0.31). TPE in patients aged ≥ 75 years is uncommon, but its tolerance is comparable to that of younger patients. When clinically indicated, TPE should not be withheld on the basis of age alone.