2013 Background: Preliminary data suggest that the use of dexamethasone, radiation and temozolomide (TMZ) in high- grade gliomas (HGG) results in substantial immunosuppression. This prospective multicenter study serially followed CD4 counts and outcomes in this population. Methods: CD4 counts were obtained from patients with HGG before initiating standard radiation and TMZ and monthly thereafter for one year. Data on hospitalizations, infections, glucocorticoid doses, survival, and cause of death were recorded. Results: 96 patients with HGG were accrued and received TMZ: 84% had glioblastoma, 80% had debulking surgery, 50% were female, 97% were Caucasian, median age was 57, and median KPS was 90. The median CD4 count before starting radiation and TMZ was 664 which fell to 347, 255, and 288 at 1, 2, and 3 months. The CD4 count nadir occurred at 2 months when CD4 counts were < 300 in 73% of patients and < 200 in 40%. CD4 counts remained low during the year of follow-up with medians of 296, 311, and 310 at 4, 8, and 12 months. Reductions in CD4 counts were mirrored by total lymphocyte counts but independent of changes in WBC, RBC, or platelets. Patients with CD4 counts < 200 at 2 months had shorter survival than those with higher counts (median 13.1 versus 19.7 months, p = 0.002). The hazard ratio for death attributable to low CD4 count was 1.99 (p = 0.003) and after adjustment for relevant factors was 1.95 (p = 0.008). Median survival was related to the CTC toxicity grades for CD4 counts: grade 1 = 23.8 months, grade 2 = 19.7 months, grade 3-4 = 13.1 months (p = 0.009). Death occurred from disease progression in 88% of the patients and infection in only 2%. The only significant pretreatment predictor for low 2-month CD4 count was low baseline CD4 count (p = 0.025). Conclusions: Standard therapy of HGG results in severe CD4 count reductions that occur early, are long-lasting, and are prognostic for early death from tumor progression. These results support the routine monitoring of CD4 counts and have important implications for studies escalating TMZ doses or using vaccines. Future studies will determine the role of CD4 counts in modifying the duration of prophylactic antibiotics and the intensity and duration of TMZ. No significant financial relationships to disclose.