Hydroxypropylmethylcellulose (HPMC) is a food gum that shares certain characteristics, such as high viscosity, with soluble fibers. In this trial, the safety and cholesterol-lowering efficacy of HPMC consumed with and between meals was evaluated in free-living male volunteers with mild-to-moderate hypercholesterolemia. After a 14-d baseline period, men (n = 51) with LDL cholesterol between 3.36 and 4.91 mmol/L and triglycerides <3.95 mmol/L were randomly assigned to consume 5.0 g/d HPMC in 240 mL of orange drink, taken either with or between meals, for a 2-wk treatment period. In the Between Meals group, total cholesterol was reduced by 8.0% vs. baseline in wk 1 of treatment (P < 0.05) and 5.1% in wk 2 (P < 0.01). LDL cholesterol concentrations fell by 12.0 and 7.7% (P < 0.01). In the With Meals group, reductions were 9.5 and 8.3% for total cholesterol, and 12.5 and 12.8% for LDL cholesterol (wk 1 and 2, respectively, P < 0.01). In both groups, HDL cholesterol decreased by approximately 5% during wk 1 of treatment (P < 0.01), but the wk 2 concentrations were not significantly different from baseline. There were no significant differences between groups in lipid responses, although there was a trend for a smaller LDL cholesterol-lowering effect during wk 2 of treatment in the Between Meals group (P < 0.06). Gastrointestinal-related adverse experiences (mostly mild) were twice as common among participants who ingested HPMC with meals (P < 0.05). These results suggest that HPMC has a lipid-lowering effect, which may be more consistent when taken with meals.