Background: Few multicity studies have evaluated the association between cold spells and mortality risk and burden. Objectives: We aimed to estimate the association between cold spells and cause-specific mortality and to evaluate the mortality burden in China. Methods: We conducted a time-series analysis with a nationally representative Disease Surveillance Points System database during the cool seasons spanning from 2013 to 2015 in 272 Chinese cities. We used 12 cold-spell definitions and overdispersed generalized additive models with distributed lag models to estimate the city-specific cumulative association of cold spells over lags of 0–28 d. We controlled for the nonlinear and lagged effects of cold temperature over 0–28 d to evaluate the added effect estimates of cold spell. We also quantified the nationwide mortality burden and pooled the estimated association at national and different climatic levels with meta-regression models. Results: For the cold-spell definition of daily mean temperatures of percentile of city-specific daily mean temperature and duration of consecutive d, the relative risks (i.e., risk ratios) associated with cold spells were 1.39 [95% confidence interval (CI): 1.15, 1.69] for non-accidental mortality, 1.66 (95% CI: 1.20, 2.31) for coronary heart disease mortality, 1.49 (95% CI: 1.12, 1.97) for stroke mortality, and 1.26 (95% CI: 0.85, 1.87) for chronic obstructive pulmonary disease mortality. Cold spells showed a maximal lagged association of 28 d with the risks peaked at 10–15 d. A statistically significant attributable fraction (AF) of non-accidental mortality [2.10% (95% CI: 0.94%, 3.04%)] was estimated. The risks were higher in the temperate continental and the temperate monsoon zones than in the subtropical monsoon zone. The elderly population was especially vulnerable to cold spells. Discussion: Our study provides evidence for the significant relative risks of non-accidental, cardiovascular, and respiratory mortality associated with cold spells. The findings on vulnerable populations and differential risks in different climatic zones may help establish region-specific forecasting systems against the hazardous impact of cold spells. https://doi.org/10.1289/EHP9284

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