Complement activation occurs in diabetic nephropathy with the downstream complement component C5a activating the innate immune system, contributing to inflammation. Resistant starch (RS) may be nephro-protective however the effects of RS on complement activation and the innate immune system have not been explored. Six week old non-diabetic mice (dbh), diabetic mice (dbdb) and dbdb mice on a regular chow diet supplemented with 25% RS (dbdbRS) were maintained for ten weeks. 24-hour urine was collected for albumin and C5a measurement by ELISA. Kidneys were digested and enriched for leukocytes using Percoll gradient and flow cytometry was performed. Diabetes was associated with an increase in albuminuria (28.0±6.5 vs 411.3±275.8µg/24h, P<0.001, dbh vs dbdb), which was reduced in diabetic mice receiving RS supplementation (411.3±275.8 vs 125.6±37.3µg/24h, P<0.01, dbdb vs dbdbRS). Urinary C5a excretion was increased by diabetes (92.6±17.6 vs 1324.0±429.7pg/24h, P<0.001, dbh vs dbdb) and decreased by RS (1324.0±429.7 vs 577.7±123.1pg/24h, P<0.05, dbdb vs dbdbRS) and infiltrating renal macrophages were more likely to be positive for C5aR with diabetes (4.8±3.9 vs 54.0±27.8%, P<0.001, dbh vs dbdb), which RS supplementation reduced (54.0±27.8 vs 11.7±4.2%, P<0.01, dbdb vs dbdbRS). These studies support the notion that RS is protective against renal disease via inhibition of complement.