Reactivation of cytomegalovirus (CMV) occurs during intensive immunosuppressive therapies. However, the influence of CMV reactivation on prognosis in patients with immunosuppressive therapies for collagen-vascular diseases (CVD) is not fully understood. To determine whether CMV reactivation affects the prognosis of patients with CVD and to identify risk factors of CMV reactivation, we reviewed, retrospectively, the medical records of 109 CVD patients who were treated with glucocorticoid (prednisolone ≥20 mg/day) and were tested for CMV antigen (CMV-Ag). CMV-Ag was detected in 34 of the 109 patients. First-time CMV-Ag detection was within 50 days from the start of intensive immunosuppressive therapy in 82% of the patients. Common manifestations at first-time CMV-Ag detection were fever, arthralgia, and rash, although 52.9% of the patients were asymptomatic. The risk factors for CMV reactivation were old age (>65 years) and high-dose glucocorticoids (PSL ≥50 mg). During the 4-year study period, 18% of patients with positive CMV-Ag and 5% of those without CMV-Ag died. Patients with CMV-Ag (max CMV number ≥5/10(5) WBC) had a significantly poorer prognosis. Multivariate analysis confirmed CMV reactivation as an independent poor prognostic factor in CVD patients. Causes of death were exacerbation of pre-existing interstitial pneumonia and infection other than CMV. Our results demonstrate that CMV reactivation, particularly with a high CMV-Ag number, is a poor prognostic factor in CVD patients. Patients with older age and high-dose glucocorticoids have a high risk of CMV reactivation.