Introduction. Focal segmental glomerulosclerosis is one of the causes of ESRD that can recur in the transplant kidney (TX). Proteinuria may recur within hours after the graft is received whereas overt sclerosis is not evident until weeks or months later. Extensive foot process effacement is sometimes the earliest sign of recurrence of FSGS. However, segmentally sclerotic glomeruli in transplant kidney could also be seen secondarily due to other causes like hypertension, chronic allograft nephropathy, chronic transplant glomerulopathy, and calcineurin inhibitor toxicity. Otherwise, it could also be considered as de novo FSGS. In this study, regarding the importance of differential diagnosis of recurrent primary FSGS (Rec FSGS) from secondary FSGS (Sec FSGS) due to the possible recurrence of FSGS in next transplant, we tried to find out the diagnostic criteria of Rec vs Sec FSGS based on clinical findings at presentation, time of diagnosis after transplant, and light microscopic and EM findings. We also studied the spectrum of different morphologic variants of FSGS in transplant kidney based on new Columbia classification. Methods. All Tx biopsies with segmental sclerosis and/ or extensive foot process effacement (FPE) and negative IF between 1995 and 2006 were reviewed excluding cases diagnosed as Tx glomerulopathy. All slides, reports, EM phothomirograph, clinical history, and follow-up reports were reviewed. Light microscopic findings were classified by the Colombia schema. Findings of Sec FSGS such as CNI toxicity, expanded lamina rara interna of GBM, and limited FPE were assessed and cases were classified as primary vs Sec FSGS. Results. Forty-two patients (29 males, 13 females) met entry criteria. Average age was 37±13.8 years (range, 11 to 56 years). Four patients were children (< 18 years old). Twenty cases (48%) were African American and 13 (31%) were Caucasian. Twenty-three (55%) had nephritic proteinuria at the time of biopsy. Biopsy interval ranged from 4 days to 8 years after Tx. Twenty-three (54%) cases were classified as Rec FSGS, 15 (35%) as Sec FSGS, and 4 (10%) as likely de novo FSGS. Ten (54%) cases showed only extensive FPE, 4 (17%) cellular (CELL), 4 (17%) collapsing (COLL), and 4 (17%) not otherwise specified (NOS) lesions. In cases classified as likely Sec FSGS, NOS lesion was the most common morphologic variant, in 6 (40%), followed by 3 (20%) COLL, 2 (13%) CELL, and 3 (20%) with only FPE. Rec FSGS was the most common in early biopsies (85% of all FSGS cases in first 6 months). In contrast, 13 (65%) biopsies at >2years showed Sec FSGS. Nearly all patients, whether Rec or Sec FSGS, lost their kidney during the following months to years. Conclusion. Early time of recurrence and extensive FPE were characteristic of Rec FSGS. NOS variant is more common in Sec, whereas extensive FPE alone is the most common finding in Rec FSGS. COLL, related to CNI toxicity, and CELL lesion can be seen in both Rec and Sec FSGS. We conclude that integrated analysis of LM, EM, and clinical data help to differentiate varying etiologies of sclerotic lesions in the Tx.