In the latter half of the fourth century, Didymus the Blind, Eunomius of Cyzicus, and Gregory of Nazianzus all responded to the position that the Holy Spirit is merely an activity of God, and not a substantial reality. Heretofore, those who held this position have remained unidentified in modern scholarship. In this article, it is argued that the fourth-century arguments derive directly from an authentic fragment (number 37) of Origen’s Commentary on John, in which Origen argues against some form of modalism, perhaps Sabellianism. Origen’s use of John 3:8 together with 1 Corinthians 12:11 became decisive for later theologians in ascribing agency to the Spirit. Despite their obvious differences, Didymus, Eunomius, and Gregory follow Origen in viewing it as imperative to speak of the Spirit as a substantial reality in order to preserve the scriptural portrayal of the Spirit as active. Accordingly, this article provides testimony to the diverse legacy of Origen in the fourth century, as well as to the function of ‘substance’ language in fourth-century doctrinal disputes.