Glioblastoma multiforme (GBM) is impossible to fully remove surgically and almost always recurs at the borders of the resection cavity, while systemic delivery of therapeutic drug levels to the brain tumour is limited by the blood-brain barrier. This research describes the development of a novel formulation of Irinotecan-loaded Drug Eluting Seeds (iDES) for insertion into the margin of the GBM resection cavity to provide a sustained high local dose with reduced systemic toxicities. We used primary GBM cells from both the tumour core and Brain Around the Tumour tissue from recurrent GBM patients to demonstrate that irinotecan is more effective than temozolomide. Irinotecan had a 75% response rate, while only 50% responded to temozolomide. With temozolomide the cell viability was never below 80% whereas irinotecan achieved cell viabilities of less than 44%. The iDES were manufactured using a hot melt extrusion process with accurate irinotecan drug loadings and the same cytotoxicity as unformulated irinotecan. The iDES released irinotecan in a sustained fashion for up to 7 days. However, only the 30, 40 and 50% w/w loaded iDES formulations released the 300 to 1000 μg of irinotecan needed to be effective in vivo. The 30 and 40% w/w iDES formulations containing 10% plasticizer and either 60 or 50% PLGA prolonged survival from 27 to 70 days in a GBM xenograft mouse resection model with no sign of tumour recurrence. The 30% w/w iDES formulations showed equivalent toxicity to a placebo in non-tumour bearing mice. This innovative drug delivery approach could transform the treatment of recurrent GBM patients by improving survival and reducing toxicity.