In the refining of crude oil, hydroprocessing units such as hydrotreaters and hydrocrackers are used to remove impurities such as sulfur, nitrogen, and metals from the crude oil. They are also used to convert the feed into valuable products such as naphtha, jet fuel, kerosene and diesel. The current invention provides very high to total conversion of heavy oils to products in a single high-pressure loop, using multiple reaction stages. A hot high pressure separator is located between the first and second reaction stages. Overhead from the separator is treated in a distillate upgrader, which may operate in co-current or countercurrent mode.