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(1) The prevention of cytomegalovirus (CMV) in lung transplant recipients (LTx) is based on the administration of VGC for a period of 6–12 months, but there is little information on the premature discontinuation of the drug. Our objective was to evaluate the reasons for early cessation of VGC and the dynamics of CMV replication after discontinuation. (2) We carried out a retrospective study of LTx on VGC prophylaxis according to guidelines, with an outpatient follow-up period of >90 days. The detection of any level of CMV-DNA in the plasma (Cobas, Roche Diagnostics®) during a period of 18 months after the discontinuation of VGC was considered positive. (3) We included 312 patients (64% male, mean age 53.50 ± 12.27; 71% D+R+, 15% D−R+, and 14% D+R−) in our study. The prescribed prophylaxis was completed by 179 patients (57.05%). The mean duration of prophylaxis was 7.17 ± 1.08 months. The recorded reasons for VGC discontinuation in 133 patients (43%) were myelotoxicity (n = 55), impaired renal function (n = 32), and gastrointestinal disturbances (n = 11). The reason for discontinuation was not recorded for 29 patients. CMV-DNA was detected in 79% (n = 246) of cases, and D+R+ and D+R− recipients showed a high risk of detection (p < 0.001). The median times to onset of CMV-DNA detection were 35 days in D+R−, 73 days in D+R+, and 96 days in D−R+ (p < 0.001). (4) Adverse effects of VGC are frequent in LTx. CMV-DNA detection is very common after the discontinuation of VGC and is related to the CMV donor and recipient serostatus.