The connection between hippocampal sclerosis and childhood febrile seizures (CFS) is a contentious issue in the study of epilepsy. We investigated 107 patients with drug-resistant epilepsy by high-resolution volumetric magnetic resonance imaging (MRI). 20 had a history of CFS, 45 had focal (26) or diffuse (19) hippocampal volume loss (HVL). The frequency of CFS was significantly (p < 0.001) higher in the patients with HVL, especially of the diffuse pattern, compared to other epileptic patients without HVL and to the general population. Furthermore, the severity of HVL was greatest in those with a history of CFS. No other clinical or demographic features were associated with either a history of CFS or HVL. The frequency of CFS in patients with other structural congenital causes of epilepsy did not differ from that in a general population. Although these findings show that hippocampal sclerosis is strongly associated with a history of CFS, they do not indicate whether this is a causal relationship. If CFS do cause some cases of hippocampal sclerosis, this can not be the only mechanism, as 64% of those with HVL gave no history of CFS. As diffuse HVL is more strongly associated with a history of CFS than focal HVL, it is also possible that CFS convert pre-existing congenital focal abnormalities into diffuse hippocampal sclerosis. Given the possibility that CFS may cause hippocampal damage and epilepsy, they require urgent medical intervention.