Profitability in crop production is largely driven by crop yield, production costs and commodity prices. The objective of this study was to quantify the often substantial yet somewhat illusive impact of weather, management, and soil spatial variability on within-field profitability in corn and soybean crop production using profitability indices for profit (net return) and return-on-investment (ROI) to produce estimates. We analyzed yield and cropping system data provided by 42 farmers within Central and North Eastern Iowa from 2007 to 2014. The dataset was comprised of 380 site years from 77 fields. Commercial software was used to calculate spatial net return (profit) in crop production, ROI, and standard deviation in profit over time for individual fields. Iowa State University Estimated Costs of Crop Production in Iowa were used to calculate profitability maps. These profitability metrics were then joined with soil attributes (organic matter, drainage, slope), site-specific rainfall, crop rotation and environmental modeling for soil conditioning index and soil loss by erosion. The relationship between profitability metrics and site-specific field and within-field factors was analyzed for two Iowa Landform Regions: the Des Moines Lobe and the Iowan Surface. Within both Landform Regions, 10 to 50% of within-field areas had economic losses, especially during 2013 and 2014. We found a higher frequency of economic loss in poorly drained pothole vs. upland areas within the Des Moines Lobe.  With each additional cm of May or June rainfall, median field-level profits were reduced by $50 to $120 ha^-1for fields planted to corn.  Compared with corn, profitability of soybean fields was unaffected by May rainfall and less affected by June rainfall. The effect of rainfall in Eastern Iowa was different than in Central Iowa, with above normal July rainfall tending to increase profitability by $43 ha^-1with each additional unit of rainfall. Other than soil drainage, we did not find a significant effect of spatial factors on within-field profitability, indicating the predominance of rainfall and cropping systems. The presented analyses are critical for guiding design and development of future studies that can lead to the creation of risk mitigation tools for farmers.