In this paper, we will study neighborhood system S-approximation spaces, i.e., combination of S-approximation spaces with identical elements except that they have different knowledge mappings, e.g., the knowledge mappings differ due to different experimental conditions and/or sampling methodology. In such situations, there is a risk of contradictory knowledge sets which can lead to different decisions by the same query. These situations are studied in this paper in detail. Moreover, neighborhood system S-approximation spaces are investigated from a three-way decisions viewpoint with respect to different deciders. In addition, completeness results are shown for optimistic and pessimistic neighborhood system S-approximation spaces, i.e., these constructions can be represented by an ordinary S-approximation space. Also, the concept of knowledge significance is proposed and studied in detail, and we have shown that computing a minimal set of knowledge mappings for a neighborhood system S-approximation space is NP-hard. Finally, the paper is concluded by two illustrative medical examples.