Background: Variable prophylaxis regimens have been adapted to guard against cytomegalovirus (CMV) after renal transplantation. High-dose valganciclovir (VGCV) is the gold standard, but it is of very high cost. Herein, we compared another low-cost regimen [low-dose valacyclovir (VCV)] with low-dose VGCV to assess the efficacy and safety of VCV. Patients and methods: This is a single-center randomized controlled trial that was held in Urology and Nephrology Center, Mansoura University, Egypt. The patients were divided into two groups according to CMV prophylaxis regimen used. Group I included 40 kidney transplant recipients who received low-dose VCV (2 g b.i.d.), and group II included 40 kidney transplant recipients who received low-dose VGCV (450 q.d.). Results: Our patients’ age ranged from 18 to 58 years, and the majority were males. The median years of transplantation were 1.9 years. Efficacy of both regimens was similar. Interruption of VCV was more frequent, with significant difference, and it was associated with increased incidence of CMV infection but without any statistical significance. The cost of low-dose VGCV was very high in comparison with low-dose VCV. Conclusion: Low-dose VCV showed the same efficacy and safety of low-dose VGCV as CMV prophylaxis protocol after kidney transplantation.