This paper attends to examine the historical materials related to smallpox in the Republic of China Daily from 1916 to 1949, in terms of the prevalence of smallpox, diagnosis and treatment, and societal responses recorded. It was found that smallpox had many different names recorded in the newspaper, and most of them related to the symptoms and the epidemic features. It was reported that smallpox, as an epidemic, occurred almost every year from 1916 to 1949. Among them, six serious outbreaks happened in 1918, 1921-1922, 1926, 1929-1930, 1932-1936, and 1946. It was found that smallpox was prevalent in winter and spring with its symptoms in the four periods: onset, rash, pustulation, and decrustation. Its treatment focused on clearing heat (Qing Re) and detoxification or warming and tonifying (Wen Bu) with traditional Chinese medicine.