Objectives To compare clinical and audiologic outcomes among patients who underwent myringoplasty with fat graft enriched with platelet-rich plasma and cartilage perichondrium graft. Study Design Prospective randomized controlled study. Setting Department of Otolaryngology-Head and Neck Surgery, Tanta University, Egypt. Subjects and Methods The study comprised 50 patients who had tympanic membrane perforation of medium size (25%-50% of its surface area) without evidence of active otitis media or ossicular abnormalities and who had surgery between December 2016 and December 2017. Patients randomly underwent myringoplasty with fat graft enriched with platelet-rich plasma (group 1) or cartilage perichondrium graft (group 2). Results Twenty-five patients were included in each group. Rates of successful closure at 3-month follow-up were 88% (group 1) and 92% (group 2). The mean overall improvement in pure tone average was 18.08 dB (95% CI, 16.9-19.25) for group 1 and 18.24 dB (95% CI, 16.94-19.53) for group 2. Conclusion Fat graft enriched with platelet-rich plasma can be recommended as an alternative choice for first-line treatment of medium-size central perforations of the tympanic membrane, with healing and hearing results comparable to those of conventional cartilage perichondrium myringoplasty.