In Colombia, there has been very little discussion about the epidemiological transition in the 20th century, therefore, there are few empirical studies, and this mainly focus on the second half of the 20th century, and on the factors associated with improvements in mortality indicators. In this paper, we define three stages of the epidemiological transition in the country during the period 1918–1998, with special emphasis on changes in mortality rates, causes of death and the contribution of different age groups. Likewise, a co-integration analysis is carried out to model the long-term relationship between the mortality rate and the variables of nutrition, public health, education and economic growth. Finally, we show the results of the structural change tests of the mortality rates for pneumonia and tuberculosis to examine the impact of the arrival of sulphonamides and penicillin in Colombia.