Diffuse WHO grade II (GIIG) may be unresectable when involving critical structures. To assess the feasibility and functional tolerance (cognition and quality of life) of an original therapeutic strategy combining neoadjuvant chemotherapy followed by surgical resection for initially inoperable GIIG. Ten patients underwent Temozolomide for unresectable GIIG, as initial treatment or at recurrence after previous partial resection, due to invasion of eloquent areas or bi-hemispheric diffusion preventing a total/subtotal removal. Functional outcome after both treatments was assessed, with evaluation of seven cognitive domains. Chemotherapy induced tumor shrinkage (median volume decrease 38.9%) in ipsilateral functional areas in six patients and in the contralateral hemisphere in four. Only four patients had a 1p19q codeletion. The tumor shrinkage made possible the resection (mean extent of resection 93.3%, 9 total or subtotal removals) of initially inoperable tumors. Postoperatively, three patients had no deficits, while verbal episodic memory and executive functions were slightly impaired in seven patients. However, global quality of life was roughly preserved on the EORTC QLQ C30 + BN 20 (median score: 66.7%). Role functioning score was relatively reduced (median score: 66.7%) whereas KPS was preserved (median score: 90, range 80–100). Seven patients became seizure-free while three improved. This combined treatment is feasible, efficient (surgery made possible by neoadjuvant chemotherapy) and well-tolerated (preservation of quality of life, no serious cognitive disturbances). Cognitive deficits seem mostly related to tumor location. Because KPS is not reliable enough, a detailed neuropsychological assessment should be systematically performed in GIIG.