The geography of research and innovation activity is a traditional topic of research in human geography. Classical studies of the clustering and diffusion of innovation in the 1960s and 70s received a new impetus in the 21st century with the understanding of the openness of innovation and the importance of interregional collaborative networks. Digitalization has played an important role, providing access to new sources of large geocoded data on the movement of key elements of the knowledge economy, including publications as a formalized outcome of scientific activity. The purpose of the article is to identify the center-periphery research ties of one of the largest macroregions of Russia – the Big South of Russia. The aim was to assess the territorial patterns of interregional research networks with the identification of gravity poles and interconnections at the local and national levels. The study uses the method of spatial scientometrics. Geocoded data on publications from the Scopus bibliographic database were used. In the course of the study the hypotheses of “Moscow-centricity” and “St. Petersburg-centricity” of the knowledge domain of the macroregion are tested, the influence of the factor of geographical proximity and the role of the diversity of interregional ties are evaluated, and the “heights-lowlands” of the landscape are revealed. The results of the research have shown a high degree of connectivity between the regions of the Big South of Russia in the research area. The hypothesis about the presence of several centers of gravity of scientific activity in the macroregion was confirmed. First of all, the peaks of the “scientific ridge” of the Big South form Rostov oblast with the largest urban agglomeration in the south of the country, the Rostov urban agglomeration, as well as the Krasnodar krai and Volgograd oblast. The hypothesis of the existence of several centers of scientific activity in the macroregion was confirmed. The influence of the factor of territorial proximity in the formation of research ties is not high and is manifested mainly in the southern Russian regions with relatively low indicators of research output (primarily, it is typical for national republics). Interregional research cooperation between advanced regions is not limited to immediate geographical proximity but is due to a combination of non-territorial factors. The “Moscow-centricity” of the scientific agenda of the regions of the Big South of Russia is true for most of the southern regions of the Russian Federation, which is particularly pronounced in regions with low internal scientific potential and in new regions undergoing a period of transformation of their scientific systems.