Co-prescription of Aerochamber® spacer with non-extrafine beclometasone diproprionate (non-EF BDP) is common but unlicensed. We report a comparison of inhaled corticosteroid (ICS)-related adverse events between patients co-prescribed Aerochamber compared to the licensed Volumatic® spacer. We utilised two historical cohorts: questionnaire-based and electronic medical record (EMR)-based, to assess patient-reported and EMR-recorded adverse events in patients with asthma prescribed non-EF BDP. Marginal effect estimate (MEE) was calculated to determine non-inferiority of Aerochamber compared to Volumatic in terms of patient-reported oral thrush and hoarseness with margin of 0.13. Other patient-reported adverse events (sore throat, bruising, weight gain, and coughing), and EMR-recorded adverse events were also assessed. Rate of patient-reported oral adverse events were non-inferior in 385 patients prescribed Aerochamber compared to 155 patients prescribed Volumatic (27.7 vs 29.9%; MEE, -0.043; 95% CI, -0.133 to 0.047). Total patient-reported adverse events did not differ significantly between Aerochamber and Volumatic (53.3 vs 49.7% with ≥1 adverse event). The EMR-based study of 1471 matched pairs of subjects did not show significantly different number of EMR-recorded adverse events between Aerochamber and Volumatic (12.5 vs 12.8% with ≥1 adverse events). Co-prescribing Aerochamber with non-EF BDP does not increase the risk for patient-reported and EMR-recorded ICS-related adverse events compared to co-prescribing Volumatic.