The lipopolysaccharide (LPS) of the cell wall of gram negative bacteria can affect different physiological pathways including lipids metabolism. The purpose of the present study was to evaluate the effects of single injection (IP) of different E. coli LPS doses on serum level of cholesterol, triglyceride, HDL-C, LDL-C and VLDL-C and study the role of sodium diclofenac on alteration of the above parameters. In this study 96, male Wistar rats were divided randomly in to 8 equal groups. Groups 1 and 2 were injected with normal saline and diclofenac (2.5 mg/kg, 1M) as control groups, respectively. Groups 3, 4 and 5 were injected (IP) with 100, 200 and 300 mg/rat of LPS, respectively. Groups 6, 7 and 8 were injected with the same amaunt of LPS as above groups and also with diclofenac (2.5 mg/kg, single dose, 1M). Blood samples were taken by heart puncture in different times periods (0, 1, 6 and 24 hrs) after LPS injection. The level of cholesterol, triglycerides, HDL-C, LDL-C and VLDL-C in plasma were measured by common biochemical enzymatic laboratory methods. Statistical analysis of the level of HDL-C showed, significant decrease in different times after LPS administration with or without diclofenac (P<0.05). The level of LDL-C showed an increase pattern in different times after LPS injection with or without diclofenac, but this finding was not statistically significant in all. The level of cholesterol, triglyceride and VLDL-C did not show significant changes (P>0.05). Preliminary results suggested that single dose of diclofenac can not prevent the HDL-C and LDL-C changes after administration of LPS in rats.