PURPOSE: To assess the systematic errors in liver methylene fraction (LMF) resulting from fat-fat interference effects with dual- and triple-echo gradient-recalled-echo Dual/Triple GRE) sequences and to test the robustness of these sequences after iron overloading. MATERIALS AND METHODS: Forty type-2 diabetic patients underwent LMF measurement by 3.0T ¹H magnetic resonance spectroscopy (corrected for T1 and T2 decays) as the reference standard and liver fat fraction (%Fat) measurement by four Dual/Triple GRE sequences with 20° and 60° flip angle (α), corrected for T1 recovery. The same four sequences were repeated in eight patients after ferumoxide injection. Corrections for systematic errors were determined from the linear regressions (spectroscopy LMF values over Dual/Triple GRE %Fat values). Robustness was tested using Wilcoxon's signed-rank test. RESULTS: Fat-fat interference effects produced a ∼10% relative systematic error and T2* decay produced a 1.9%-4.2% absolute systematic error in LMF. When comparing before and after ferumoxide, dual-echo imaging with α = 20° and α = 60°, even when corrected, showed absolute differences of 7.23% [2.81%-10.25%] (P = 0.0117) and 5.65% [1.89%-8.216.8%] (P = 0.0117), respectively; compared to only 1.17% [0.08%-2.83%] (P = 0.0251) and 1.15% [0.37%-2.73%] (P = 0.2626) with triple-echo imaging and α = 20° and α = 60°, respectively. CONCLUSION: Triple-echo imaging with α = 60° corrected for both T1 recovery and fat-fat interference effects is robust after superparamagnetic iron oxide (SPIO) administration and can reliably quantify LMF.