Over the last three decades, there has been special interest in developing drugs that mimic the characteristics of natural tears for use it in the treatment of several ocular surface disorders. Interestingly, the composition of blood plasma is very similar to tears. Therefore, different blood-derived products like autologous serum (AS) and plasma rich in growth factors (PRGF) have been developed for the treatment of diverse ocular pathologies. However, scarce studies have been carried out to analyze the differences between both types of blood-derived products. In the present study, blood from three healthy donors was drawn and processed to obtain AS and PRGF eye drops. Then, human corneal stromal keratocytes (HK) were treated with PRGF or undiluted AS. Proteomic analysis was carried out to analyze and characterize the differential protein profiles between PRGF and AS, and the differentially expressed proteins in HK cells after PRGF and AS treatment. The results obtained in the present study show that undiluted AS induces the activation of different pathways related to an inflammatory, angiogenic, oxidative stress and scarring response in HK cells regarding PRGF. These results suggest that PRGF could be a better alternative than AS for the treatment of ocular surface disorders.