Using the middle atmosphere temperature data set observed by the Sounding of the Atmosphere using Broadband Emission Radiometry (SABER) satellite experiment between 2002 and 2012, and temperatures simulated by the Whole Atmospheric Community Climate Model version 3.5 (WACCM3.5) between 1953 and 2005, we studied the influence of El Niño-Southern Oscillation (ENSO) on middle atmosphere temperature during the Northern Hemisphere (NH) wintertime. For the first time, a significant winter temperature response to ENSO in the middle mesosphere has been observed, with an anomalous warming of ~1.0 K/MEI (Multivariate ENSO Index) in the tropics and an anomalous cooling of ~ −2.0 K/MEI in the NH middle latitudes. The observed temperature responses to ENSO in the mesosphere are opposite to those in the stratosphere, in agreement with previous modeling studies. Temperature responses to ENSO observed by SABER show similar patterns to those simulated by the WACCM3.5 model. Analysis of the WACCM3.5 residual mean meridional circulation response to ENSO reveals a significant downwelling in the tropical mesosphere and upwelling in the NH middle and high latitudes during warm ENSO events, which is mostly driven by anomalous eastward gravity wave forcing in the NH mesosphere.