There is a growing interest in the use of soil microbial inoculants as an alternative biological approach to a) improve soil quality, b) enhance the growth, yield and quality of crops, and c) reduce the inputs of chemical fertilizers and pesticides in agriculture worldwide. One such product that has received considerable attention, is Effective Microorganisms or EM; it consists of mixed cultures of beneficial microorganisms. A long-term field experiment was conducted at Faisalabad, Pakistan to determine the agronomic and economic merits of EM in a rice-wheat cropping system. Treatments were applied in a randomized complete block design that included: control (untreated); recommended chemical fertilizer (NPK); green manure (GM); farmyard manure (FYM); Effective Microorganisms (EM) alone; NPK + EM; GM + EM; and FYM + EM. Significantly higher grain and straw yields for both crops were obtained with NPK alone, with other treatments in the following order: NPK > GM > FYM > EM. However, when fertilizer and organic amendments were combined with EM, higher grain and straw yields were obtained for each crop following the same order, i.e., NPK+EM > GM+EM > FYM+EM. The GM+EM treatment produced grain and straw yields for each crop that approached those for NPK alone. In all cases, the grain and straw yields from EM alone were higher than the controls. With few exceptions, EM applied in combination with NPK, GM and FYM caused a significant increase in nutrient uptake by the grain and straw of each crop. The uptake of NPK by both crops was higher for EM alone than for the controls. A comparative economic analysis of the treatments showed a significantly higher net return due to EM. The average net profit from rice and wheat production using EM was $44.90 ha−1 and $62.35 ha−1, respectively. The study indicates that EM can enhance maximum economic yields in a rice-wheat rotation and also improve soil productivity when applied with organic amendments.