Most patients with non-lesional temporal lobe epilepsy (NLTLE) will have the findings of hippocampal sclerosis (HS) on a high resolution MRI. However, a significant minority of patients with NLTLE and electroclinically well-lateralized temporal lobe seizures have no evidence of HS on MRI. Many of these patients have concordant hypometabolism on fluorodeoxyglucose-PET (18FFDG-PET). The pathophysiological basis of this latter group remains uncertain. We aimed to determine whether NLTLE without HS on MRI represents a variant of or a different clinicopathological syndrome from that of NLTLE with HS on MRI. The clinical, EEG, 18FFDG-PET, histopathological and surgical outcomes of 30 consecutive NLTLE patients with well-lateralized EEG but without HS on MRI (HS−ve TLE) were compared with 30 consecutive age- and sex-matched NLTLE patients with well-lateralized EEG with HS on MRI (HS+ve TLE). Both the HS+ve TLE group and the HS−ve TLE patients had a high degree of 18FFDG-PET concordant lateralization (26 out of 30 HS−ve TLE versus 27 out of 27 HS+ve TLE). HS−ve TLE patients had more widespread hypometabolism on 18FFDG-PET by blinded visual analysis odds ratio (OR = +∞ (2.51, −), P = 0.001. The HS−ve TLE group less frequently had a history of febrile convulsions OR = 0.077 (0.002–0.512), P = 0.002, more commonly had a delta rhythm at ictal onset OR = 3.67 (0.97–20.47), P = 0.057, and less frequently had histopathological evidence of HS OR = 0 (0–0.85), P = 0.031. There was no significant difference in surgical outcome despite half of those without HS having a hippocampal-sparing procedure. Based on the findings outlined, HS−ve PET-positive TLE may be a surgically remediable syndrome distinct from HS+ve TLE, with a pathophysiological basis that primarily involves lateral temporal neocortical rather than mesial temporal structures.