A pharmacovigilance study analyzed data from the FAERS and CVARD databases on immunosuppressive adverse events (IRAEs) in the treatment of glioblastoma with the combination of bevacizumab (BEV) and temozolomide (TMZ). Overall, there were 1,076 reports in the BEV + TMZ group, 2,633 in BEV monotherapy, and 3,156 in TMZ monotherapy. Combination therapy showed strong disproportionality signals for rare immunosuppressive and opportunistic infections, such as hemophagocytic lymphohistiocytosis (HLH; Ω = 0.648), strongyloidosis (Ω = 0.744), Epstein-Barr virus infection (Ω = 0), and cytomegalitis (Ω = 0.943). Analysis of interactions indicated more than additive signals for hematologic (eg, pancytopenia) and non-hematologic (eg, enteritis) toxicities. The time to onset of lymphocytopenia shifted from 34 days with BEV monotherapy to 23 days with the combination. Multivariable logistic regression showed a higher odds of reporting IRAEs with BEV monotherapy versus TMZ (OR = 3.6037, 95% CI: 1.0378–12.652, p < 0.05), with no significant difference versus the combination. Signals require prospective confirmation and do not demonstrate causality.