This paper analyzes the determinant factors of R&D collaboration between firms and knowledge institutions in South Africa. For this we use the South African National Innovation Survey of 2008. In contrast to findings from research conducted in advanced countries, we find that foreign-owned companies more likely collaborate with knowledge institutions. However, these foreign multinationals do not more likely engage in cooperative research agreements with local knowledge institutions. Hence, host country governments in developing countries should aim to induce foreign firms to collaborate with local research centers and local universities by, for example, improving the human and physical resources available at these organizations. We also find that appropriability concerns do not prevent industry-science cooperative research agreements. Furthermore, whether a firm collaborates in R&D with universities or public research organizations depends on the specific industry in which a firm operates. Firms in the mining industry, financial intermediaries, and R&D companies are more likely to be involved in cooperative research agreements. Finally, R&D collaboration with knowledge institutions is complementary to the innovation strategy of sourcing publicly available information.