Although the expression of T-cell antigens and proteins associated with tumor-infiltrating T-lymphocytes (TILs), regulatory T cells (T-regs), and B-cell development have been evaluated in classical Hodgkin lymphoma (cHL), few studies correlate these proteins' expression patterns with clinical outcome. The purpose of this study was to evaluate proteins expressed in the Reed-Sternberg cells (RSCs) and TILs of cHLs at initial diagnosis to determine their prognostic significance. The expression of 12 proteins in RSCs and TILs from 88 diagnostic cHL biopsies was quantitated and correlated to overall survival (OS) and progression-free survival (PFS). CD2, CD3, CD4, CD5, CD7, CD25, PD1, TIA1, MUM1, and ZAP70 expression in RSCs did not correlate with OS or PFS, nor did programmed death 1 (PD1) expression in TILs. High numbers of TIA1-positive TILs (≥50%) correlated with OS (P=0.027), but not PFS (P=0.993) in univariate analysis. Expression of CD2, CD3, CD4, CD5, and/or TIA1 (6%) in RSCs was associated with lymphocyte-rich/mixed-cellularity subtype (P=0.032). High International Prognostic Score (IPS; P=0.036), and high stage (P=0.046) were independent predictors of worse PFS in univariate analysis. Low IPS (P=0.003) and nodular sclerosing subtype (P=0.022) were associated with better OS in univariate analysis. Only the IPS predicted OS in multivariate (P=0.009) analysis. High TIA1+ TILs correlated with worse clinical outcomes for cHLs, as did PAX5-RSCs (P=0.024), although only 2/74 cases were shown to be negative for this marker, suggesting that the tumor microenvironment and a transcription factor crucial for B-cell development are critical biological determinants of the disease course.