Background: BCC rarely metastasizes and the mortality rate is low; however, the disease is associated with substantial morbidity. Transforming growth factor-b1 (TGF-b1) is a key player in cell proliferation, differentiation, apoptosis, and immune regulation. TGF-b1 is associated with immunosuppression and resistance to immunotherapeutic drugs. Immune checkpoint proteins (ICMs) maintain self-tolerance and modulate the immune responses of effector cells. The current study compared the levels and possible associations between systemic soluble ICMs (sICMs) and a group of humoral modulators of immune suppressor cells in a cohort of patients with advanced basal cell carcinoma (BCC, n = 40) and a group of healthy control subjects (n = 20). Methods: We measured sICMs and immunosuppressive humoral modulators by using multiplex bead array or ELISA procedures, with plasma as the matrix. The sICMs comprised seven co-inhibitory (CTLA-4, BTLA, LAG-3, PD-1, PDL-1, PDL-2, and TIM-3) and eight co-stimulatory (CD27, CD28, CD40, CD80, CD86, GITR, GITRL, and ICOS) proteins, as well as the two dual-active sICPs, HVEM and TLR2. The seven humoral modulators of immunosuppressor cells included arginase 1, fibroblast activation protein (FAP), RANTES (Regulated upon Activation Normal T Cell Expressed and Presumably Secreted) also known as CCL5, interleukin-10 (IL-10), TGF-b1, and the M2-type macrophage biomarkers, soluble CD163 (sCD163) and sCD206. Ethics approval was granted by The Research Ethics Committee, Faculty of Health Sciences, University of Pretoria (Ethics Committee Approval Numbers 356/2020. Results: The plasma levels of six co-inhibitory sICPs, sCTLA-4, sLAG-3, sPD-1, sPD-L1, and sTIM-3 and sPD-L2 were significantly elevated in the cohort of BCC patients (p< 0.001-p< 0.00001), while that of sBTLA was significantly decreased (p< 0.006). Of the co-stimulatory sICPs, sCD27 was significantly increased (p <0.0002) in the cohort of BCC patients, with the levels of the others essentially comparable with those of the control patients; of the dual active sICPs, sHVEM, sTLR2 was significantly elevated (p< 0.00001) and TLR2 comparable with the control group. Although the plasma levels of the seven modulators of immune suppressor function were not significantly different between the BCC and control groups, correlation heat maps revealed selective, strong associations of TGF-b1 with seven co-stimulatory (z = 0.618468-0.768131) and 4 co-inhibitory (z = 0.674040-0.808365) sICPs, as well as with sTLR2 (z = 0.696431). Conclusions: Notwithstanding the association of BCC with selective elevations in the levels of a large group of co-inhibitory sICPs, our novel findings also imply the probable involvement of TGF-b1 in driving immunosuppression in this malignancy, possibly via activation of regulatory T cells.