Coastal flood risk assessments typically ignore interannual to multidecadal variability stemming from mean sea level, storm surges, and long period tides (i.e. 4.4 year perigean and 18.6 year nodal cycles), although combined these can lead to significant variations in extreme sea levels (ESL). Here, we examine the effects of ESL variability on the amplification of flood frequencies and risks for 17 major U.S. coastal cities. We also quantify the relative importance of ESL variability compared to long-term relative sea level rise (RSLR). Results show that, depending on the region, observed ESL variability can lead to amplification factors of up to 79, indicating that the 100 year return period event can become a 1.26 year event during certain time periods when ESL variability peaks high. Additionally, depending on the RSLR scenario considered, the observed range of ESL variability is equivalent to the RSLR projected to occur over the next few years in some locations and several decades (up to 2100) in others. These ESL fluctuations also modulate flood risk estimates, with the aggregated 100 year flood losses for the 17 major U.S. coastal cities changing by up to US$ 141 979 million (or 28%). This study demonstrates the importance of including ESL variability in regional coastal flood risk assessments; it highlights the importance of being aware and vigilant of these variations when observed and projected ESL situations are quantified assuming that certain sea level components are stationary.