Objectives  To examine the implementation of nonpharmaceutical interventions for epidemic mitigation in 43 cities in the continental United States from September 8, 1918, through February 22, 1919, and to determine whether city-to-city variation in mortality was associated with the timing, duration, and combination of nonpharmaceutical interventions; altered population susceptibility associated with prior pandemic waves; age and sex distribution; and population size and density.

Design and Setting  Historical archival research, and statistical and epidemiological analyses. Nonpharmaceutical interventions were grouped into 3 major categories: school closure; cancellation of public gatherings; and isolation and quarantine.

Main Outcome Measures  Weekly excess death rate (EDR); time from the activation of nonpharmaceutical interventions to the first peak EDR; the first peak weekly EDR; and cumulative EDR during the entire 24-week study period.

Results  There were 115 340 excess pneumonia and influenza deaths (EDR, 500/100 000 population) in the 43 cities during the 24 weeks analyzed. Every city adopted at least 1 of the 3 major categories of nonpharmaceutical interventions. School closure and public gathering bans activated concurrently represented the most common combination implemented in 34 cities (79%); this combination had a median duration of 4 weeks (range, 1-10 weeks) and was significantly associated with reductions in weekly EDR. The cities that implemented nonpharmaceutical interventions earlier had greater delays in reaching peak mortality (Spearman r = –0.74, P < .001), lower peak mortality rates (Spearman r = 0.31, P = .02), and lower total mortality (Spearman r = 0.37, P = .008). There was a statistically significant association between increased duration of nonpharmaceutical interventions and a reduced total mortality burden (Spearman r = –0.39, P = .005).

Conclusions  These findings demonstrate a strong association between early, sustained, and layered application of nonpharmaceutical interventions and mitigating the consequences of the 1918-1919 influenza pandemic in the United States. In planning for future severe influenza pandemics, nonpharmaceutical interventions should be considered for inclusion as companion measures to developing effective vaccines and medications for prophylaxis and treatment.