In today’s ever-changing and highly uncertain environment, organizations depend on research and development (R&D) activities to adapt intensive growth of technology. One of the most important and trickiest tasks of any developing firms is to define new projects. This process gets difficult when it comes to choosing an appropriate portfolio from a set of candidate projects. Since organizations are faced with limited resources of R&D and budget constraints, they have to choose a project portfolio that mitigates the corresponding risk and enhances the overall value of portfolio. Therefore, the purpose of this study is to introduce a practical model to select the best and the most proper project portfolio while considering project investment capital, return rate, and risk. The ever-changing and highly uncertain environment of projects is addressed by utilizing interval type-2 fuzzy sets (IT2FSs). In this paper, a new model of R&D project evaluation is first introduced. This model includes a new risk-return index. This model is then extended in project portfolio selection, and as a result, a new model of R&D project portfolio selection is proposed under uncertainty. Constraints and limitations of R&D project portfolio selection are comprehensively addressed. In this model, lower semi-variance is applied to consider risk of proposed projects. Therefore, this paper offers a new model that applies IT2FSs to handle uncertainty, uses semi-variance to assess risk, synchronously considers risk and return in its selection process, and addresses the considerations and limits of real-world problems. Eventually, to verify the proposed model, a numerical example of the existing literature is solved with the model, and the results are compared. The first proposed model is used to prioritize proposed R&D projects of a gas and oil development holding firm as a real case study. To illustrate further, a practical example is also provided to demonstrate the applicability of the proposed project portfolio selection model.