The aberrant activation of T lymphocyte proliferation is one of the key events in organ transplant recipients and autoimmune disorders. The present study adopted a gel-based proteomics approach to define the proteins representative of the T cell proliferation and to discover the molecules that play critical roles during the suppression of T cell proliferation. Human T lymphocytes were isolated from healthy donors and primed with phytohemagglutinin (PHA) to undergo proliferation. Two medical fungal products with specific T cell activation inhibitory properties, cyclosporine A (CsA) and polysaccharopeptide (PSP), were used to study the proteins that manipulate T cell proliferation. After demonstrating their similar effects on cell proliferation, cell survival and interleuklin-2 (IL-2) secretion, significant quantitative protein alterations were detected between the CsA- and PSP-treated T cell proteome. These altered proteins were identified by MALDI-TOF and classified into 3 categories: (i) proteins affected by both CsA and PSP, (ii) proteins affected by CsA alone, and (iii) proteins affected by PSP alone. Most of these altered proteins have functional significance in protein degradation, the antioxidant pathway, energy metabolism and immune cell regulation.