Hepatitis A virus (HAV) and Hepatitis E virus (HEV) are transmitted through the fecal–oral route. HAV outbreaks and one HEV outbreak have been reported in Egypt. However, the impact of HAV–HEV co-infection is not known. In this study, we assessed HEV markers in acute HAV-infected patients (n = 57) enrolled in Assiut University hospitals. We found that 36.8% of HAV-infected patients were also positive for HEV markers (anti-HEV IgM and HEV RNA), while 63.2% of the patients were HAV mono-infected. Demographic and clinical criteria were comparable in both HAV mono-infected patients and HAV–HEV co-infected patients. Although liver enzymes were not significantly different between the two groups, liver transaminases were higher in the co-infected patients. Six patients developed acute liver failure (ALF); five of them were HAV–HEV-co-infected patients. The relative risk of ALF development was 8.5 times higher in HAV–HEV co-infection compared to mono-infection. Three cases of ALF caused by HAV–HEV co-infection were reported in children (below 18 years) and two cases were reported in adults. All patients developed jaundice, coagulopathy, and encephalopathy; all were living in rural communities. In conclusion: HAV–HEV co-infection can be complicated by ALF. The risk of ALF development in HAV-infected patients is higher when coinfection with HEV is present.