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Abstract Background Carpal tunnel syndrome (CTS) is the most common upper limb entrapment neuropathy caused by compression of the median nerve as it traverses the wrist at the carpal tunnel. Objectives To compare the effect of single dose of platelet-rich plasma (PRP) injected locally with that of corticosteroid in patients with CTS. Subjects and methods A total of 60 patients with very mild to moderate unilateral CTS were recruited to the study. PRP was prepared via two centrifugation procedures. The patients were randomly divided into three groups PRP [i] group, PRP [ii] group, and a third group that received local corticosteroid injection (CS). The patients were followed up at 1.5 and 3 months by visual analog scale (VAS) for pain assessment. The severity and functional outcomes were evaluated through Boston CTS, and neurophysiological analyses were carried out. Results On comparing the PRP [i], PRP [ii], and CS groups, a statistically significant enhancement of all outcome variables was observed in both PRP groups at follow-up except VAS at 3 and 6 months (P = 0.073 and P = 0.068, respectively) in PRP [ii] group. Conclusion In CTS, PRP was a better treatment alternative with respect to pain and functional outcome. In addition, it was associated well with improved neurophysiological values than those observed after corticosteroid injection. Trial registration Zagazig University, ZU-IRB#5014. Registered 18 December 2018, http://www.IRB_123@medicine.zu.edu.eg. ISRCTN Registry, ISRCTN16755281 ; 20 March 2020