Soybean [Glycine max L.] is a valuable crop, providing protein, oil, and income for farmers. Despite the significance of crop in study area, there was lack of knowledge on crop and response to B. japonicum. The study was conducted at Maale district of South omo zone southern Ethiopia to investigate the response of soybean varieties to B. japonicum. It was consisted of a factorial combination of seven soybean varieties namely, Awassa-95, Nyala, Nova, Awassa-04, Gozella, Afgat, and Pawe-2 with two levels of inoculation, with and without B. japonicum. A randomized complete block design (RCBD) with three replications was used. Data were collected on phonological, nodule, growth, yield, and yield related parameters. The analysis of variance showed all measured parameters, except the number of seed pod-1 such as canopy spread, plant height, number of primary branches, number of nodules, number of effective nodules, above ground biomass yield, 1000 seed weight, harvest index, were significantly (p< 0.01) affected by B. japonicum. The interaction of varieties with B.japonicum were also significantly affected the number of pod plant-1 and grain yield ha-1.The maximum grain yield (2017.50 kg ha-1) was recorded from Awasssa-04 with B. japonicum. Based on the economic analysis, Awassa-95, Nova and Nyala variety with B. japonicum gave the higher value of economic return respectively, however, these varieties gave a lower grain yield. Therefore, a combination of Awassa-04 with B.japonicum is ideal for achieving maximum grain yield and Awassa-95, Nova and Nyala with B.japonicum was economically feasible options.