Root-knot nematode infestations tend to be spatially clustered within agricultural fields and result in crop yield penalties. Site-specific nematode management provides the opportunity for producers to maximize profit while maintaining acceptable yield and reducing overuse of product. This paper determines the potential of site-specific nematicide application by using spatial econometric analysis of on-farm experiments data to estimate cotton yield response functions with respect to environmental factors and treatment applications. The results suggest that yield response for nematicide application differs by soil texture. The post-treatment nematode population at bloom season and percent sand fraction are significant factors in explaining yield variability. Spatial spillovers from neighboring plots also significantly impact yield estimates. The results can be used to provide practical recommendations for effectively controlling nematodes via site-specific management.