Chemo‐induced thrombocytopenia is a limiting toxicity among patients receiving temozolomide (TMZ) as first‐line treatment for glioblastoma. We aimed to compare early platelet concentration kinetics, hematological safety profile, and impact on survival following the initiation of either the brand‐name or a generic TMZ formulation. A retrospective trial was conducted in patients suffering from newly diagnosed glioblastoma. Patients were treated with TMZ at 75 mg/m2 per day during six weeks, concomitantly with radiotherapy. Platelet concentration was collected each week. Primary endpoint was to perform a linear mixed‐effect model of platelet concentration kinetic over weeks. A total of 147 patients were included as follows: 96 received the brand‐name TMZ, and 51 received a generic TMZ formulation. Exposition to the generic was a significant variable that negatively influenced the platelet kinetics in the radiotherapy and concomitant TMZ phase, P = 0.02. Grade ≥3 chemo‐induced thrombocytopenia was more frequent in the generic group: 19.6% 95% CI 8.7‐30.5% vs 3.1% 0‐6.6%, P = 0.001. Exposition to the generic formulation of TMZ led to increase early treatment discontinuation due to TMZ‐induced thrombocytopenia and was a worsening independent prognostic factor on overall survival: adjusted HR 1.83 1.21‐2.8, P = 0.031. These data suggest that exposition to a generic formulation of TMZ vs the brand‐name product is associated with higher early platelet decrease leading to clinically relevant impacts on treatment schedule in glioblastoma. Further prospective trials are needed to confirm these results.