Objectives: The purpose of this study was to compare the surgical outcomes of Polycel® and titanium in ossiculoplasty following tympanomastoidectomy (TM). Methods: A total of 221 patients underwent ossiculoplasty following TM by a single surgeon using either Polycel® or titanium as prosthesis. Hearing was tested preoperatively and postoperatively at 6 months by pure-tone audiometry. Successful surgery was defined if postoperative air-bone gap (ABG) was <20 dB, the gain in air conduction (AC) hearing was >15 dB HL, or postoperative AC was <30 dB HL. Multiple linear regression was conducted to identify the factors associated with the surgical outcomes. Results: In canal wall up mastoidectomy (CWUM), both Polycel® and titanium showed favorable successful rates if partial ossicular replacement prosthesis (PORP) was used (64.3% of Polycel® and 67.6% in titanium). If total ossicular replacement prosthesis (TORP) was used, both represented similar outcomes (54.5% of Polycel® and 75.0% in titanium). In canal wall down mastoidectomy (CWDM), significant ABG reductions were observed only in the titanium group (5.2 ± 14.7 dB of Polycel® [P =.083] and 7.0 ± 14.2 dB of titanium [P =.002] in PORP; 4.6 ± 13.5 dB of Polycel® [P =.097] and 9.5 ± 11.2 dB of titanium [P <.001] in TORP). In multivariate analysis, titanium had a positive effect on the reduction of postoperative AC thresholds (B: −4.772; 95% CI: −8.706-−0.838). Conclusions: Both Polycel® and titanium showed favorable surgical outcomes for ossiculoplasty following CWUM. Titanium prosthesis is recommended for surgery after CWDM.