Objective Chronic graft-versus-host disease (cGVHD) is the main cause of late non-relapse mortality following hematopoietic cell transplantation. Oral mucosal (om-) cGVHD is common, but diagnosis and assessment rely on clinical interpretation and patient-reported symptoms. We investigated immunohistopathological profiles with respect to om-cGVHD severity disease duration. Material and methods Ninety-four transplant patients and 15 healthy controls (n = 212 biopsies) were investigated by quantitative immunohistochemistry for T cells (CD4, CD8, and CD5), B cells (CD19 and CD20), macrophages (CD68), and Langerhans cells (CD1a). Results We found significant increases in T (CD4, CD8) and monocytic (CD68) cells in om-cGVHD, and a notable absence of B (CD19 and CD20) cells. Histopathological activity correlated with increased CD4, CD8 and CD68. However, CD4 was associated with mild om-cGVHD, whereas CD8 and CD68 were found to be elevated in severe om-cGVHD. CD8 and CD68 levels were raised at disease onset, but during late phase, the predominant CD68 population was accompanied by CD4. Conclusion Oral cGVHD is a heterogenous clinical disorder, but our knowledge of the underlying biology remains limited. We highlight the importance of CD4, CD8 and CD68 immune profiling, together with histological grading for the staging of oral cGVHD, to broaden our understanding of the biology and individual disease course.