Increased delivery of circulating free fatty acids (FFA) to the liver has been implicated in the pathogenesis and progression of diabetes. The liver is inaccessible for direct measurement in humans in vivo. We measured liver FFA uptake with positron emission tomography (PET) and 14( R, S)-[(18)F]fluoro-6-thia-heptadecanoic acid ([(18)F]FTHA) in healthy men. We evaluated the use of graphical analysis and linear fit to describe uptake data over time, and compared the use of metabolite-corrected vs uncorrected input functions. Rapid accumulation of tracer in the liver was observed with time, leading to progressively higher tissue to blood radioactivity ratios. Using metabolite-corrected input function curves, linear fit to the data ( r value) exceeded 0.99 in all subjects, during each fitting time frame. Values of liver FFA influx rate constant and uptake were 0.34+/-0.01 ml min(-1) ml(-1) and 0.20+/-0.02 micro mol min(-1) ml(-1), respectively, and were minimally affected by the choice of the fitting interval. Expressed per unit mass, liver FFA uptake was ~50 times higher than that reported in skeletal muscle; in the whole organ, FFA uptake was twice as high as in skeletal muscles. The use of metabolite-uncorrected input functions significantly worsened the spread of data around the fitted line and led to a remarkable underestimation of liver FFA uptake at all time intervals. In conclusion, our data provide non-invasive quantification of hepatic FFA uptake in humans, showing the liver to handle a high FFA flux. [(18)F]FTHA-PET appears a valuable tool for the investigation of hepatic FFA turnover in humans.