Background: Nephrotic range proteinuria, segmental obliteration or collapse of glomerular capillary loops in some glomeruli, and increased extracellular matrix are the hallmarks of the podocytopathy known as focal and segmental glomerulosclerosis (FSGS). Objective: This research set out to determine if the matrix metalloproteinase inhibitor doxycycline (DOX) could be useful in the management of primary focal segmental glomerulosclerosis. Patients and Methods: This prospective cohort study was conducted on 100 patients with primary FSGS, who were recruited from Nephrology Department at Benha University Hospital. Informed consents were signed after getting approval from the Ethics Committee of Benha University. Inclusion criteria were age >18 years, primary FSGS, diagnosis is confirmed by renal biopsy, patients with overt albuminuria (A/C ratio>30 mg/g and urinary albumin > 30 mg/day). Results: The hemoglobin level was significantly higher at follow-up compared to baseline level in group 1 (P=0.026) and was insignificantly different between baseline and at follow-up in group 2. Hemoglobin level at baseline and follow-up was insignificantly different between both groups. C-reactive protein was significantly lower at follow-up compared to baseline level in group 1 and 2 (P<0.001). C-reactive protein was significantly lower at follow-up in group 2 compared to group 1 (P<0.001) and was insignificantly different between both groups at baseline. Platelet count and white blood cells were insignificantly different between baseline and at follow-up in both groups. There was an insignificant difference between both groups regarding platelet count and white blood cells at baseline and at follow-up < strong>. Conclusions: Patients who received DOX alongside conventional therapy exhibited notable improvements in clinical and biochemical parameters, including reduced proteinuria and enhanced kidney function, compared to those receiving conventional therapy alone. These findings suggest that DOX may hold promise as a supplementary treatment strategy for FS.