Primary recovery of therapeutic proteins from mammalian cell culture remains one of the most challenging steps in downstream processing due to ever increasing advances in upstream technology, leading to higher titers, but also higher cell density and, oftentimes, lower viability. One of the most common techniques used to clarify cell culture is centrifugation followed by depth filtration. However, because of the large capital expenditure a centrifuge requires, a disposable depth filtration train capable of handling cell culture directly is an attractive alternative under some circumstances. In this work, the performance of depth filtration of mammalian cell culture without centrifugation was evaluated. Two different style depth filter trains were used - a coarse train with a large pore size distribution for non-centrifuged material, and a fine train with a smaller pore size distribution for centrifuged material. The different trains were evaluated over numerous mammalian cell culture harvests of various monoclonal antibodies (mAbs) for capacity and clarification of the feed stream. As expected, the direct filtration of mammalian cell culture resulted in lower capacity, as well as greater sensitivity to variations in the cell culture. However, centrifugation itself was seen to have a clear impact on the filterability of the product stream. The selection of appropriate filter types to address these variations will be discussed.