BACKGROUND AND OBJECTIVE: To determine possible changes in thickness profiles of retinal layers in patients with rhegmatogenous retinal detachment (RRD) treated with perfluoropropane (C3F8) or silicon oil (SiO). PATIENTS AND METHODS: Seventy-two eyes of 36 patients were enrolled in this retrospective comparative study. Patients were divided into two groups according to intraocular tamponade: C3F8 or SiO. All study eyes were compared with fellow eyes via spectral-domain optical coherence tomography segment analysis at 6 months postoperatively. Macular layer thicknesses including retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), and retinal pigment epithelium were analyzed. RESULTS: There was a statistically significant difference between eyes in terms of INL thickness (P = .044) in C3F8 group. Otherwise there was a statistically significant difference between eyes in terms of INL, OPL, and ONL thicknesses (P = .006, P = .048, and P = .004, respectively) in the SiO group. CONCLUSION: The findings of the present study show that the tamponade used in RRD surgery can affect the retinal layers differently.