Birth defects (BDs) are structural or functional anomalies, sporadic or hereditary, of prenatal origin. Public health surveillance is defined as the ongoing systematic collection, analysis, and interpretation of outcome-specific data for use in the planning, implementation, and evaluation of public health practice. BD surveillance systems may have different characteristics according to design, coverage, type of surveillance, case ascertainment, case definition, BD description, maximum age of diagnosis, pregnancy outcomes, coding systems, and the location of the coding process (central or local). The aim of this article is to describe and compare methodology, applications, and results of birth defect surveillance systems in two South-American countries: Colombia and Argentina. In both countries, the surveillance systems developed activities in relation to the Zika virus emergency. For most BDs, a statistically significant higher prevalence is observed in Argentina-RENAC than in Colombian registries. This may be due to methodological reasons or real differences in prevalence. The strengths, weaknesses, and the future perspectives of the Argentine and Colombian systems are presented. When developing a surveillance system, the objectives, the available resources, and previous experiences in similar contexts must be taken into account. In that sense, the experience of Argentina and Colombia can be useful for others when developing a birth defect surveillance system.