A challenging aspect with the use of the Sp2/0 hybridoma cell line in commercial manufacturing processes of recombinant therapeutic proteins is their exogenous lipids requirement for cell proliferation and optimal protein secretion. Lipids are commonly provided to the culture using serum or serum-derivatives, such as lipoprotein supplement. The batch-to-batch variability of these non-chemically defined raw-materials is known to impact cell culture process performance. Lipoprotein supplement variability and its impact on fed-batch production of a recombinant monoclonal antibody (mAb) expressed in Sp2/0 cells were studied using 36 batches from the same vendor. Several batches were associated with early viability drops leading to low process performance during fed-batch production. Increased caspase-3 activity (an indicator of apoptosis) was correlated to viability drops when low-performing batches were used. Addition of an antioxidant to the culture limited the increase in caspase-3 activity. Physicochemical characterization of batches confirmed that lipoproteins are mainly composed of lipids and proteins; no clear correlation between low-performing batches and lipoprotein supplement composition was observed. Controlled lipoprotein oxidation leads to lipoprotein solution browning, increasing absorbance at 276 nm and results in poor process performance. Because low-performing batches absorb more at 276 nm than other batches, oxidized lipids were suspected to be the root cause of low-performing batches. This study increased the understanding of lipoprotein supplement composition, its sensitivity to oxidation and its impact on process performance.