Background: Recurrent glioblastoma (GBM) has dismal outcomes and limited treatment options. Mebendazole (MBZ) is an anti-helminthic drug with in-vivo and in-vitro activity against glioma cell lines and has been demonstrated to be well tolerated in combination with lomustine (CCNU) and temozolomide (TMZ). In this phase 2 study, we sought to determine whether the addition of MBZ to CCNU or TMZ would improve overall survival (OS) in recurrent GBM. Methods: Adult patients with ECOG PS 0-3, with recurrent glioblastoma who were not eligible for re-radiation, were randomized 1:1 between CCNU-MBZ (n = 44) and TMZ-MBZ (n = 44). The primary endpoint was OS at 9 months, selected to reflect the BELOB trial. A 9-month OS of 55% or more in any arm was hypothesized to warrant further evaluation and a value below 35% was too low to warrant further investigation. Results: At 17.4 months, 68 events for OS analysis had occurred. The 9-month overall survival was 36.6% (95%CI 22.3-51) and 45% (95%CI 29.6-59.2) in the TMZ-MBZ and CCNU-MBZ arms respectively. ECOG PS was the only independent prognostic factor impacting OS (HR-0.478 95%CI 0.268-0.851; P = 0.012). Twenty-three patients (28.6%) enrolled had an ECOG PS 2-3 with inferior outcomes (median OS-5.67, HR-2.092 95%CI 1.175-3.731). Analysis restricted to ECOG PS 0-1 (n = 65) patients revealed a 9-month OS of 39.6% (95% CI 22.4-56.3) and 57.9% (95% CI 38.7-73) in TMZ-MBZ and CCNU-MBZ arms respectively. Grade 3-5 adverse events were seen in 8 (18.6%; n = 43) and 4 (9.5%; n = 42) patients in the TMZ-MBZ and CCNU-MBZ arms respectively. Conclusions: The addition of MBZ to TMZ or CCNU failed to achieve the pre-set benchmark of 55% 9-month OS. This was probably due to 28.6% of patients with poor PS of 2-3. In patients with ECOG PS 0-1, CCNU-MBZ had a 9 month OS of 57.9% and needs to be evaluated further. Clinical trial information: CTRI/2018/01/011542.