This randomized, multiple cross‐over pharmacokinetic study was undertaken to determine if food or sucralfate alter the bioavailability of the active S(+) enantiomer of Ibuprofen. Eleven healthy adult male volunteers were given three single 600‐mg doses of ibuprofen (separated by 1 week) administered either in a fasting state, after a standardized breakfast, or with sucralfate 1 g. The main outcome measures were area under the concentration (AUC), maximum peak plasma concentration (Cmax), and time to reach peak concentration (tmax) for total, S(+), and R(−) enantiomer serum ibuprofen levels, drawn up to 10 hours after dosing. The AUC for R(−) ibuprofen was significantly lower than S(+) ibuprofen in all three treatment groups. The treatments had no different effects on AUC for S(+), R(+), or total ibuprofen. There was no difference in the ratio of S(+):R(−) enantiomers across different treatment groups, but the intersubject variability was significant (P <.05). The S(+) ibuprofen Cmax was greater than the R(−) ibuprofen Cmax for ail treatment groups (P <.05). Sucralfate reduced the peak concentration of both S(+) and R(−) enantiomers when compared with fasting (P <.05). There was a slight but nonsignificant increase in the mean time to achieve peak concentration of both S(+) and R(−) enantiomers. Neither food nor sucralfate has a significant effect on ibuprofen enantiomer pharmacokinetics, but interindividual variability contributes significantly to the variability of enantiomer bioavailability.