Background: This study aimed to investigate whether there are differences in the axonal degeneration rate between patients in the early years of relapsing-remitting multiple sclerosis (RRMS) disease and RRMS patients in their later years. Methods: The early-stage RRMS patients (EMS) group had 65 patients whose duration of disease was within 3 years from the date of the first attack. The late-stage RRMS patients (LMS) group had 69 patients whose duration of disease was within the range of 3-10 years from the date of the first attack. In addition, a control group was composed of 32 healthy subjects. Peripapillary retinal nerve fiber layer (RNFL) thickness was monitored with spectral-domain OCT in all included patients for approximately 3 years. Results: The annual RNFL atrophy rate (aRNFLr) in the EMS group was -1.246 +/- 0.778 mu m/year, the aRNFLr in the LMS group was -0.898 +/- 0.536 mu m/year, and the aRNFLr was -0.234 +/- 0.154 mu m/year in the control group (p < 0.001). The aRNFLr in the EMS group was significantly higher than the aRNFLr in the LMS group (p = 0.01). The aRNFLr was not associated with MRI activity or the condition of having an attack. There was a correlation between Expanded Disability Status Scale (EDSS) progression and aRNFLr in both the EMS and LMS patient groups (r = -0.471, p < 0.001, and r = -0.567, p < 0.001, respectively). Conclusion: The axonal degeneration rate is faster in RRMS patients in the first years of the disease than in later years. In addition, axonal degeneration occurs independently of inflammatory activity. Axonal degeneration is correlated with disability progression, but not with inflammatory findings, such as clinical episodes and MRI activity.