Direct adsorption of lipoproteins (DALI) apheresis is the first method for direct adsorption of lipoproteins from whole blood and is therefore an easy and rapid procedure. The majority of patients reaches >60% acute low-density lipoprotein cholesterol (LDL-C) reduction using either the DALI 750 or 1000 configuration. However, in patients with extremely high LDL-C levels or very large blood volumes, these configurations may lead to suboptimal results. The current study was performed to test the safety and efficacy of DALI 1250. In a severely obese patient (185 cm, 133 kg, blood volume 7.2 L, LDL-C 239 mg/dl), 11 L of blood (1.53-fold patient blood volume) was processed at a flow rate of 80 ml/min in 2.5 h; a combined heparin-plus-citrate anticoagulation regimen was used. Commercially available DALI 1250 and DALI hardware and disposables were manufactured by Fresenius HemoCare Adsorber Technology, St. Wendel, Germany. Twenty weekly sessions were performed. Clinically and technically, the apheresis sessions were completely uneventful. As compared to DALI 1000 (n = 4 sessions), the reduction rates by DALI 1250 (n = 20) improved for LDL-C (from 52% to 66%), lipoprotein (a) (Lp[a]) (53% vs. 66%), and fibrinogen (11% vs. 16%). There was a slight increase in high-density lipoprotein cholesterol (HDL-C) loss (20% vs. 24%). Moreover, the absolute amount of LDL-C removed per session increased from 5.06 g to 5.94 g. Laboratory safety parameters remained within the normal range, the anticoagulation was well controlled, and the pressure gradients over the adsorber remained constant. In this case report, DALI 1250 was perfectly safe and significantly increased the efficacy of LDL-C and Lp(a) elimination compared to standard DALI. Thus, this high-efficiency version of DALI may be used in patients with extremely high LDL-C levels and/or large blood volumes.