Twins represent a powerful resource for revealing multifactorial mechanisms in human diseases. Few reports are available on nephrotic syndrome in twins, and most furnish only a partial description of genetic identity based on human leukocyte antigens (HLA) analysis. We describe two pairs of mono and dizygotic twins with nephrotic syndrome who presented discordant outcomes in terms of length and required therapies. In one case, evolution to focal glomerulosclerosis was also documented. The basic molecular work-up included analysis of concordance based on 10 polymorphic markers (D3S1358, vVA, FGA, amelogenin, D8S1179, D21S11, D18S51, D5S818, D13S317, D7S820) and exclusion of the major slit-diaphragm gene mutation (NPHS2, CD2AP, WT1) causing nephrotic syndrome. To our knowledge, this is the first description of long-term outcome in mono- and dizygotic twins with proven genetic concordance. Discordant outcomes indicate a major influence of environmental and/or epigenetic multifactorial mechanisms on persistence and evolution of the disease to focal-segmental glomerulosclerosis.