The article analyzes regional factors that influence the development of high-tech business in Russia. The empirical basis of the study was the revenue indicators of companies in high-tech and knowledge-intensive sectors in the SPARK database, and regional economic development indicators published by Rosstat. The results of the analysis of the general characteristics of the sampling of companies showed that Russian high-tech business is mainly represented by knowledge-intensive services and is characterized by territorial unevenness. Significant territorial differentiation is also illustrated by the coefficient of regional localization of high-tech business, comparing regional relative indicators with the national value. The impact of regional conditions was assessed by five groups of factors reflecting the “regional profile,” the human resources of the region, its investment potential, scientific and innovative potential, and characteristics of digital infrastructure. Using econometric methods, it has been shown that the development of high-tech business in the region is positively influenced by factors such as a high share of manufacturing in the economy, the availability of personnel with secondary vocational education, the availability of computers for employees, staff involvement in research and development, and technological innovations. According to the calculation results, the characteristics of the scientific and innovative potential have the most significant impact on the high-tech sector.