Global Navigation Satellite System radio occultation signals often show extremely strong levels of scintillation when passing through the ionospheric E region. This is related to sporadic E(Es)—dense layers of metallic ions that can form in the E region, influencing terrestrial and satellite radio propagation. In our report on the 2007–2014 variation of E region S4 amplitude fluctuation indices measured by the FORMOSAT-3/Constellation Observing System for Meteorology Ionosphere and Climate (COSMIC) satellite constellation, we find that the spatial and temporal variation of the maximum S4 index in the E region is proportionate to the occurrence rate of extreme scintillation and by extension, sporadic E. We also find that the monthly median extreme S4 amplitude fluctuation index in the E region midlatitudes shows a dependence on variation of the El Niño–Southern Oscillation (ENSO) in the troposphere that has not been previously reported. The ENSO-related variation of the E region median extreme S4 indices varies closely with the tropopause height, with both parameters lagging the Oceanic Niño Index by roughly 1 to 2 months, while also displaying a similar spectrum of periodicities. This similarity is especially strong in the southern midlatitudes. These results indicate that ENSO signatures can be transmitted to Es formation mechanisms, potentially through modulation of vertically propagating atmospheric tides that alter lower thermospheric wind shears. The end result is the modulation of the interannual variation of extreme Es values by ENSO.