The majority of previous Regional Innovation System (RIS) studies generally provide a rather static overview of the roles of innovation-creating actors. This article explores a single RIS in Trentino in Italy. The case shows that the roles of three actors (i.e., the provincial government, academia/research centers, and firms) are vital in creating the RIS, and that the provincial-level government policy is important in supporting the innovation activities of regional research institutions and firms aimed at developing their international connections. The public-private research collaboration and international connections of these actors are the key determinants of the development of an advanced RIS, but have largely been ignored in the extant RIS literature. This article extends the existing RIS and Triple Helix research to an international dimension, highlighting the complementary role of international connections within the RIS, thus reflecting a shift toward Quadruple Helix.