Compression stockings/socks are one of the most essential materials to treat vascular disorders in veins. However, the comfort of wearing such stockings over prolonged period of time is a major problem. There is limited research in the area of comfort optimization while retaining the compressional performance. The current work is carried out with an aim to determine the optimum level of the input factors e.g., knitting structure, plaiting yarn linear density and main yarn linear density for achieving desired stretch recovery percentage and thermo-physiological comfort properties of compression socks used in treatment of vascular disorders. Their optimum combination was determined by using Taguchi based techniques for order of preference by similarity to ideal solution i.e., TOPIS. In this study, thickness, areal density, air permeability, thermal resistance, over all moisture management capacity (OMMC), stretch and recovery % were optimized simultaneously by using Taguchi-TOPSIS method. The results showed that linear density of plaiting and main yarn has significant influence on all the comfort related properties for compression stockings/socks. The optimum sample had linear density 20 denier for Lycra covered by 70 denier of nylon 66 in the plaiting yarn. It also suggested 120 denier nylon 66 in the main yarn knitted into a plain single jersey structure. The percentage contribution of the factors i.e., structure, plaiting yarn linear density and main yarn linear density was obtained by using ANOVA which are 7%, 31% and 42% respectively. It is worth mentioning that in case of compression stockings, the main yarn linear density has more significant effect on comfort properties as compared to other independent parameters. The results were verified by experiment, and the accuracy was relatively high (maximum error 8.533%). This study helped to select suitable knit structure with the change of linear densities of plaiting yarn and main yarn for comfortable compression stocking/sock and will fulfill the potential requirement for treatment of venous/vascular disorders. The novel methodology involving TOPSIS method helped in analyzing the cumulative contribution of the input parameters to achieve optimum compression as well as comfort performance. This modern approach is based on contemporary scientific principles and statistical approximations. This study may provide benchmark solutions to complex problems involving multiple interdependent criteria.