Hand, foot, and mouth disease (HFMD) is mainly epidemic in China and Southeast Asian countries. A novel enterovirus 71 vaccine has been available in China for preventing severe HFMD since 2016. Knowledge of the dynamic epidemiology of HFMD in different regions is necessary for appropriate intervention strategies. This study focused on the citywide surveillance data on the epidemiology and etiology of HFMD in Shanghai during 2014-2016. In these 3 years, the total numbers of reported HFMD cases were 65,018, 39,702, and 57,548, respectively; the numbers of severe cases (case-severity ratios) were 248 (0.38%), 35 (0.09%), and 59 (0.10%), respectively. Children <6 years old accounted for 86.65% to 89.34% of HFMD cases and 91.53 to 97.14% of severe cases. EV-A71 caused all three fatal cases. In severe cases, the detection rate of EV-A71 was 77.82% in 2014, 100% in 2015 and 98.31% in 2016. In uncomplicated inpatient cases, the detection rates of EV-A71, CV-A16, CV-A6, and CV-A10 were, respectively, 43.40, 22.10, 30.73, and 1.89% in 2014; 28.52, 6.46, 53.61, and 7.98% in 2015; and 31.79, 14.15, 44.55, and 4.64% in 2016. In mild community cases, the detection rates of EV-A71, CV-A16, CV-A6, and CV-A10 were, respectively, 25.78, 41.64, 22.93, and 1.78% in 2014; 17.41, 21.23, 50.99, and 3.15% in 2015; and 18.92, 27.84, 45.11, and 1.64% in 2016. Among the cluster outbreaks, the most common pathogen was CV-A16 in 2014 (50.69%) and 2015 (38.10%) and CV-A6 in 2016 (36.30%). These findings show that HFMD outbreaks remained at a high level in Shanghai during 2014-2016. CV-A6 was emerging as the most common pathogen causing HFMD.