This retrospective follow-up study evaluates the efficacy and safety of bioactive glass (BAG) S53P4 when applied as filler material in mastoid obliteration surgery performed on non-cholesteatomatous chronic otitis media (NC-COM) patients with chronically discharging ears despite conservative therapy. 94 Patients (96 ears) were included. Patients underwent either intact canal wall (ICW) or canal wall down (CWD) mastoid surgery between 2005 and 2015. The intervention group comprised 23 patients (23 ears) who were treated with additional mastoid obliteration using BAG S53P4; the remaining 71 patients (73 ears) were considered controls. All patients underwent preoperative CT scanning of the mastoid. Primary functional outcome, as defined by control of suppuration, was assessed using Merchant's scale. Hearing results as measured by air-bone gap and the incidence of adverse events were assessed as secondary outcomes. Thirty-two ears (44%) in the control group (n = 73) achieved complete control of infection at the most recent postoperative clinic visit vs 17 (74%) in the S53P4 obliteration group (n = 23). Comparing these outcomes yielded an odds ratio (OR) of 3.6 (p = 0.012, 95% CI 1.3-10.3). Complete failure to manage infection significantly differed (p = 0.048) between the control group (11 ears; 15%) and the S53P4 obliteration group (0 ears). No adverse events were observed in either group. Pre- and postoperative ABG results did not differ significantly between groups. Obliteration of the mastoid cavity using BAG S53P4 along with mastoidectomy in patients with chronically discharging NC-COM significantly improves the achievement of a dry and safe ear as compared to mastoidectomy alone. Importantly, no adverse events were observed with S53P4 BAG obliteration.