To determine the latest information on the soluble programmed death-1 (sPD-1) and soluble programmed death-ligand 1 (sPD-L1) immune checkpoints, we assessed the benefits and role of these two soluble proteins in various diseases. Eighty clinical studies in humans were discovered in the initial search among the 201 articles selected from the Pubmed electronic database. We grouped 80 clinical studies based on their disease pathophysiology, and selected 5 groups namely cancer, acute infectious/inflammatory, chronic infectious/inflammatory, autoimmune, and other diseases. Plasma or serum concentration is a common parameter used to assess the level of sPD-1/sPD-L1. In this review we discuss the comparison of sPD-1/sPD-L1 level in patients compared to healthy subjects, the correlation between the level of soluble form and membrane-bound PD-L1, as well as their association with the severity of diseases, treatment response, and other inflammatory markers. The sPD-1 and sPD-L1 significantly increased in cancer patients, and in patients with acute and chronic infection/inflammation. The increase also correlated with its bound shape in membrane and can assess the pathogenesis of disease and treatment response, except for the role of sPD-1 in the cancer treatment response which requires further studies. In autoimmune patients, diverse sPD-1 and sPD-L1 were reported compared with healthy subjects. A relatively small number of samples might be the cause. However, the same relationship was shown by all clinical studies in all diseases, reporting that increase in sPD-1/sPD-L1 correlated with markers of inflammatory indicators, like c-reactive protein (CRP) and various inflammatory cytokines. Since an increase in inflammatory markers occurred in other diseases such as metabolic syndrome disease, more clinical studies are required to confirm the correlation with sPD-1/sPD-L1.