We conducted a study aimed at a direct comparison of the plasma dynamics and uptake of docosahexaenoic (DHA) and oleic (OA) fatty acids by various organs. 14C-DHA and 3H-OA were intravenously co-injected into mice. At 5 min after injection, more than 40% of the 14C-DHA, but less than 20% of the 3H-OA, labels was associated with the liver. Heart uptake of 14C-DHA was three to four times greater compared to the 3H-OA label. Brain incorporation of 14C-DHA slowly rose to 0.7% at 24 h, but it remained at the 1-1.5% level for 3H-OA. Total 14C activity in plasma reached 2% of the injected dose at 20 min and leveled off at 0.5% after 1.5 h. Fifteen percent of 14C-DHA plasma activity at 30 min was associated with non-esterified fatty acids, whereas about 85% was recovered in triglycerides in very low-density lipoprotein (VLDL) and LDL fractions. Only 30% of 3H-OA derived activity was found in the VLDL fraction at 30 min. All 3H activity in plasma at later time points was in catabolite fractions. These findings demonstrate that liver plays an important role in the initial selectivity for DHA. It is likely that DHA is specifically taken up by liver, esterified, loaded into lipoproteins, and then delivered to brain, heart, and other target tissues.