Streptococcus pneumoniae (pneumococcus) is the most common cause of pneumonia and a major cause of meningitis globally. Pneumococcal conjugate vaccines (PCVs) offer protection against disease caused by selected pneumococcal serotypes and the World Health Organization (WHO) recommends the introduction of PCV as a priority. PCV10 and PCV13 have been available for over a decade, yet there is a paucity of head-to-head data to assist countries with decision-making regarding vaccine choice. We designed and conducted a randomised controlled trial in Ho Chi Minh City, Vietnam, to directly compare the immunogenicity, reactogenicity, and effect on pneumococcal carriage of a 2+1 schedule of PCV10 and PCV13. We showed that both vaccines are safe, highly immunogenic, and reduce carriage of vaccine serotypes. Some differences between vaccines were observed. PCV10 tended to be more immunogenic after the first dose and PCV13 tended to be more immunogenic post-primary series and post-booster. The clinical implications of these differences are unknown. There were trends towards a greater impact on carriage of PCV10-serotypes with PCV10 and a greater impact on carriage of PCV13-only-serotypes with PCV13. This resulted in a similar overall impact on carriage of PCV13-serotypes with both vaccines that is likely to generate substantial herd protection effects. Shared-serotype 6B and PCV13-only-serotype 6A were the two most commonly carried serotypes among unvaccinated children. The relative contribution of these two serotypes to serogroup 6 disease could be an important factor in vaccine choice in this setting. Overall, based on data from our trial, we would expect the introduction of either PCV10 or PCV13 in a 2+1 schedule to have significant public health benefits, offering both direct protection to vaccinees and indirect herd protection to the broader population. With the introduction of new PCVs to the market, more head-to-head data will be needed to assist with growing vaccine choice.