Indoxyl sulfate (IS) and p-cresyl sulfate (p-CS) are albumin-bound uremic toxins that are difficult to remove by hemodialysis (HD). Human serum albumin (HSA) carries several compounds, including fatty acids that can bind to site II of HSA and represent competing ligands for uremic toxins. The aim of this study was to investigate the association between fatty acids and uremic toxin plasma levels in patients undergoing HD. Thirty-three HD patients (51.5% male, 54.9 ± 10.2 years old, 44.63 ± 28.4 months on HD, albumin level of 3.8 ± 0.3 g/dL) were evaluated. The erythrocyte fatty acid content (saturated fatty acid [SFA], monounsaturated fatty acid [MUFA], and polyunsaturated fatty acid [PUFA]) was measured by gas chromatography, and total IS and p-CS plasma levels were measured by reversed-phase high-performance liquid chromatography. The mean percentages of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) + DHA and gamma-linolenic (GLA) acid in the erythrocyte membrane were 1.35% ± 0.74%, 1.85% ± 0.79%, and 0.33% ± 0.26%, respectively. The mean levels of IS and p-CS were 19.4 ± 11.9 mg/dL and 101.5 ± 57.2 mg/dL, respectively. There was no significant association between SFA and MUFA and IS and p-CS; however, a negative correlation was found between p-CS and specific PUFAs, and the association between GLA and p-CS levels was retained after adjusting for potential confounding variables (β = -0.49, P = 0.007). Polyunsaturated fatty acids may contribute to the decrease in p-CS uremic toxin plasma levels in patients with chronic kidney disease undergoing HD.