OBJECTIVE: To investigate the effect of water suppression on the hepatic lipid quantification, using the LCModel. MATERIALS AND METHODS: MR spectra with and without water suppression were acquired in the liver of mice at 4.7 T and patients at 3 T, and processed with the LCModel. The Cramér-Rao Lower Bound (CRLB) values of the seven lipid resonances were determined to assess the impact of water suppression on hepatic lipid quantification. A paired t test was used for comparison between the CRLBs obtained with and without water suppression. RESULTS: For the preclinical data, in the high (low) fat fraction subset an overall impairment in hepatic lipid quantification, i.e. an increase of CRLBs (no significant change of CRLBs) was observed in spectra acquired with water suppression. For the clinical data, there were no substantial changes in the CRLB with water suppression. Because (1) the water suppression does not overall improve the quantification of the lipid resonances and (2) the MR spectrum without water suppression is always acquired for fat fraction calculation, the optimal data-acquisition strategy for liver MRS is to acquire only the MR spectrum without water suppression. CONCLUSION: For quantification of hepatic lipid resonances, it is advantageous to perform MR spectroscopy without water suppression in a clinical and preclinical scenario (at moderate fields)