Abstract: Variability in soil properties across agricultural landscapes in interaction with annual climatic variations affects crop response to N fertilizer applications and is a major challenge for development of effective N fertilizer practices that increase crop yield and reduce environmental N losses. The objectives of this research were to assess spatial differences in soil N availability in fields with poorly drained claypan soils containing low-lying or depressional areas and to determine the spatial variability in relative crop response and economic returns with application of enhanced-efficiency N fertilizers (EEF) compared with those of urea. A field trial (planted with corn (Zea mays L.)) was conducted in 2007 and 2008 in a claypan soil in northeastern Missouri that contained both side slope and low-lying landscape positions. Preplant N fertilizer treatments consisted of a nontreated control and 168 kg N ha−1 of urea, polymer-coated urea (PCU), urea + urease inhibitor (UI), and urea + nitrification inhibitor (NI). Grain yield response across landscape positions was ranked PCU > NI ≥ UI ≥ urea for 2007 and PCU > UI ≥ NI ≥ urea in 2008. Further mapping of yield differences from EEF compared with those of urea indicated areas of the field with yield benefits of up to approximately 5,100 kg ha−1 in 2007 and 7,100 kg ha−1 in 2008 with application of PCU, but some areas of negative yield differences were also observed. A variable-source N fertilizer strategy with use of EEF targeted to specific landscape positions and conventional N fertilizers used in the other parts of the field may be a possible management option in claypan soils or other poorly drained soils that include depressional or low-lying areas.