The classical Hodgkin lymphoma (cHL) tumor microenvironment includes a variable inflammatory response consisting of eosinophils, mast cells, macrophages, regulatory T lymphocytes (Treg) and active lymphocytes. We counted these inflammatory cells in tumor tissue from 459 patients with cHL from Sweden and Denmark, with complete clinical data available for 409 patients. Depending on the predominant cell types and their immunologic function we categorized the immune profile into an active, anergic or innate immune response with the aim to investigate if a specific tumor immune profile can predict survival. Time to progression (TTP) (primary progression, relapse or cHL death) and overall survival (OS) were analyzed using Cox proportional hazards regression. During follow-up (median 12.9 years) 49 patients had disease progression and 78 patients died. A high proportion of Treg (an anergic immune response) conferred shorter TTP when adjusted for age (hazard ratio (HR)=2.25; 95% confidence interval (CI) 1.15-4.41), especially in advanced stages (HR=2.83; 95%CI 1.25-6.40). In addition, a low proportion of Treg combined with a high proportion of macrophages conferred superior TTP when adjusted for age, stage, albumin and bulky tumor (HR=0.23; 95%CI 0.07-0.77). This is the first study to show that a tumor microenvironment characterized by an anergic immune response corresponds to a shorter TTP in cHL, indicating a reduced ability of an anergic immune system to attack the tumor cells. The programmed death receptor 1 (PD-1) is expressed by Treg, and these results warrant further investigation to determine if Treg is a predictor of response to PD-1 blocking drugs.