Food and feed legislations are implemented to control the level of unwanted persistent organic pollutants (POPs) below health risk concerns. Short-path distillation is established as the most effective industrial process to remove POPs in fish oil. However, the technology involves heating of the oil to high temperature levels (>200 °C) that possibly give unwanted heat-induced side reactions and coevaporation of minor compounds of importance for the nutritional quality of the oil. The effects on retention of vitamins, cholesterol, and unsaponifiable compounds, geometrical isomerization, loss of polyunsaturated fatty acids (PUFA), oxidation level, and oxidative stability have been studied on the basis of experiments designed to optimize and model the effect of process conditions (i.e., evaporator temperature, feed rate, and addition of working fluid) on the reduction of POPs. Loss of volatile nutrients was observed, but the extent will depend on the process conditions needed to obtain target decontamination level, as well as the concentration ratio and difference in vapor pressure between free and esterified forms of the studied compounds. Some reduction in oxidation level was documented with preservation of PUFA level and quality. Oxidative stability was influenced both positively and negatively depending on the applied process conditions. Generally, no adverse negative effects on the nutritional quality of the fish oil could be documented. Optimal process conditions were modeled that ensure removal of POPs to within legislation levels while retaining most of the vitamin levels in fish oil. A 76% reduction of the WHO-PCDD/F-PCB-TEQ level in the used feedstock was needed to be in accordance with the voluntary industrial monograph of GOED. This could be achieved on the basis of operation conditions giving <20% loss of vitamins. A 90% decontamination rate gave vitamin retentions in the 60-90% range.