Fertilizer use remains very low in most of Africa despite widespread agreement that much higher use rates are required for sustained agricultural productivity growth. This study estimates maize yield response functions in agro-ecological Zone IIA, a relatively high potential zone of Zambia, to determine the profitability of fertilizer use under a range of small farm conditions found within this zone. The theoretical framework used in this study incorporates agronomic principles of the crop growth process. The model distinguishes different roles of inputs and non-input factors in crop production. We estimate the effects of conventional production inputs as well as household characteristics and government programs on maize yield for households in the dominant acrisols soil type. Results indicate that even within this particular soil type within Zone IIA, the maize-fertilizer response rate in the two specific years varied widely across households. The main factors explaining the variability in maize-fertilizer response rates were the rate of application, the timeliness of fertilizer availability, the use of animal draught power during land preparation, and whether the household incurred the death of an adult member in the past three years. These modifying factors, as well as variations in input and output prices due to proximity to roads and markets, substantially affected the profitability of fertilizer use on maize. Fertilizer use on maize tended to be unprofitable at full commercial fertilizer prices for farmers who received fertilizer late and who were located in relatively remote areas.