Purpose: The aim of the study was to compare the difference in composition between 100% autologous serum (AS) and 100% platelet-rich plasma (PRP) eye drops and assess their impact on the clinical outcomes after the treatment of severe dry eye (DE) in primary Sjogren Syndrome patients (pSS). Materials and Methods: This is an interventional, non-randomized, comparative, three-month study. 22 patients with severe DE in pSS were treated with 100% AS (22 eyes) and 100% PRP (22 eyes) eye drops 5 times per day in monotherapy mode. The quantifications of growth factors (GFs) such as fibroblast growth factor (FGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), transforming growth factor (TGF-b), insulin-like growth factor (IGF), fibronectin, and substancepin hemoderivates were done. The main outcome measures were: Ocular Surface Disease Index (OSDI), Best Corrected Visual Acuity (BCVA), the Schirmer test, tear break-up time (TBUT), corneal and conjunctival staining according to the Oxford scale, conjunctival hyperaemia, and Meibomian gland parameters. The results were compared at baseline, 1 month, and 3 months following the treatment. The clinical results were correlated with the concentration of GFs in the biological tear substitutes. Results: Significant differences were observed in the concentration of FGF (4.42 ± 0.86 vs. 15.96 ± 7.63,p< 0.0001), EGF (4.98 ± 0.97 vs. 39.06 ± 20.18,p< 0.0001), fibronectin (929.6 ± 111.5 vs. 823.64 ± 98.49,p= 0.0005), VEGF (175.45 ± 65.93 vs. 717.35 ± 488.15,p< 0.0001), PDGF AB (619.6 ± 117.30 vs. 349.66 ± 79.82,p< 0.0001), NGF (85.22 ± 23.49 vs. 8.29 ± 9.06,p< 0.0001), PDGF (935.38 ± 434.26 vs. 126.66 ± 54.41,p< 0.0001), substancep(112.58 ± 27.28 vs. 127.51 ± 26.56,p= 0.0125) in PRP compared to AS. The level of TGF-β was undoubtedly higher in AS than in PRP (1031.37 ± 330.23 vs. 726.03 ± 298.95,p= 0.0004). No significant differences between AS and PRP were observed in the concentration of IGF. Therapy with blood products relieved the signs and symptoms in pSS DE patients. There was a statistically significant improvement in BCVA, the Schirmer test, TBUT, Meibomian gland parameters, and the reduction of the OSDI scores, Oxford staining, and conjunctiva hyperaemia in each of the groups. However, the clinical changes were more significant in the PRP group. There were numerous correlations between the level of GFs and the mean change in clinical outcomes. No adverse events were reported. Conclusions: Despite the fact that blood derivatives differ in composition, they seem to be effective and safe in the treatment of severe DE in pSS patients. The signs and symptoms of DE were reduced in both groups, but only the mean change in OSDI was statistically significant. A greater reduction in OSDI scores was observed in the PRP group. The obtained results and the composition of haemoderivates may indicate the superiority of PRP in relieving the symptoms of DE in pSS patients compared to AS.