Research has evaluated the relative profitability of variable-rate (VRT) versus uniform-rate (URT) application of a single input in fields with multiple management zones. This study addresses map-based VRT decisions for multiple inputs in fields with multiple management zones. The decision-making framework is illustrated for nitrogen and water applied to irrigated cotton in fields with three management zones. Results suggest traditional methods of determining VRT application of a single input may by suboptimal if interactions exist among VRT inputs and URT inputs. Implications are that a systems approach to multiple-input VRT decisions can produce increased net returns to VRT.