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Background Hippocampal sclerosis is the most common cause of drug-resistant epilepsy amenable for surgical treatment and seizure control. This study aimed to analyze morbidities related to surgery of mesial temporal lobe epilepsy associated with hippocampal sclerosis and to identify possible risk factors for complications. Methods A retrospective analysis of postoperative complications was made for 389 operations performed between 1990 and 2015 on patients aged 15–67 years (mean 36.8). Three surgical approaches were used: anterior temporal lobectomy (ATL) ( n = 209), transcortical selective amygdalohippocampectomy (SAH) ( n = 144), and transsylvian SAH ( n = 36). Complications were classified as minor or major if there was a neurologic impairment or if further surgical or medical treatment was necessary. Results Complications followed 15.4% of operations. They were classed as major for 4.1% of patients, but there were no mortalities. Persistent neurologic deficits occurred in 0.5% of patients. In 3 cases (0.8%) additional surgery was necessary to treat an intracranial hematoma, a delayed hydrocephalus, and a subdural empyema. Symptomatic visual field defects (VFDs) were frequent and included contralateral superior quadrantanopia (8.2%) or hemianopia (1.3%). Overall complications ( P = 0.04) and symptomatic VFDs ( P = 0.04) were most frequent in operations on men. Major complications occurred most often with the ATL surgical approach than with transcortical SAH ( P = 0.03). Conclusions Major complications occur rarely after mesial temporal surgery on epileptic patients. They occur more often following the ATL rather than transcortical SAH approach. Complications tend to be temporary with symptoms of limited duration for surgery performed by experienced teams on carefully selected and evaluated patients. [ABSTRACT FROM AUTHOR]