Nematode management for cotton production has eluded farmers and researchers. Control strategies typically rely upon highly toxic nematicide application. Site-specific management provides opportunity to improve profitability while maintaining environmental stewardship. This paper determined the potential for site-specific nematicide application by using spatial econometric analyses of on-farm experimental data to estimate cotton yield response functions with respect to environmental factors and treatment applications. Results suggest that crop yield response for a given nematode infestation level or nematicide application rate differs by soil texture, providing evidence to support the potential of site-specific nematicide application and management zone delineation. The profitability analysis related is useful to provide practical recommendations for effectively controlling nematodes via site-specific management.