Hydrophobic hollow fiber membranes were systematically investigated in two different operation modes including microfiltration (MF) and membrane distillation (MD). Using synthetic feed waters containing model foulants, wastewater secondary effluent, and seawater, the differences in fouling behaviors and its reversibility for the membranes between MF and MD operation modes were compared. Our results demonstrate that fouling patterns in MF were completely different from those in MD. The rates of flux decline were higher in MF than in MD in most cases. No flux declines were observed by model foulants such as alginate, humic acid, and kaolin in MD although thick foulant layers were observed by SEM analysis. This can be attributed to the difference in water transport mechanisms between MF and MD. It was found that the flux decline due to the foulants in the wastewater was more reversible in MD than in MF and could be recovered, not only by chemical cleaning but also by physical cleaning.