BACKGROUND: For CMV high-risk constellations, guidelines recommend 3-6 months of prophylaxis with valganciclovir (VGCV). Management in preventing CMV primary infection in patients developing VGCV-associated leukopenia remains challenging. METHODS: We retrospectively analyzed the development of leukopenia during VGCV prophylaxis in 57 seronegative kidney recipients of a CMV-seropositive donor between 2008 and 2021. We analyzed CMV risk and development of CMV-specific T cells in the first post-transplant year depending on leukopenia during VGCV prophylaxis and management with CMV-IVIg. RESULTS: Leukopenia developed in 19/57 patients, with a significant difference in leukocyte counts occurring after 10 weeks of VGCV prophylaxis compared to patients without leukopenia (p = 0.0003). VGCV discontinuation led to leukocyte reconstitution, which tended to be faster in patients receiving additional prophylaxis with CMV-IVIg after VGCV discontinuation (n = 11, p = 0.083). In the first post-transplant year, patients with leukopenia had no higher risk for severe CMV events. Interestingly, patients receiving CMV-IVIg prophylaxis showed a significantly lower peak CMV-load during primary infection (p = 0.040), with no difference in CMV-specific T-cell levels compared to patients without leukopenia or patients with additional CMV-IVIg prophylaxis (p = 0.972). Patients developing adequate CMV-specific T-cell responses less frequently underwent CMV reactivation 50 days following primary infection. CONCLUSION: Leukopenia developed late during VGCV prophylaxis and did not result in an increased risk for CMV primary infections or severe disease. Leukopenic patients receiving CMV-IVIg tended to have a faster leukocyte reconstitution and had lower peak DNAemia, which did not adversely affect CMV-specific T-cell induction. CMV-IVIg may therefore be considered as an alternative prophylactic strategy in patients with VGCV-associated leukopenia.