Maize (Zea mays L.) is an important smallholder crop in Uganda. Yields are low because of low soil fertility and little fertilizer use. Yield response to nutrient application and economically optimal rates (EOxR, where x = N, P, or K) and N use efficiency (NUE) were evaluated. Twenty-two trials were conducted in four agroecological zones. Yield was consistently increased with N application. Mean maize yield with no N applied (N₀) was 1.79 Mg ha⁻¹ and increased by 120% with N application. Mean EONRs were 45 to 24 kg ha⁻¹ N with fertilizer use cost to grain price ratios (CPs) of 10 to 30. With N applied, the mean increase in yield due to P application was 0.28 Mg ha⁻¹ and mean EOPRs were 9 to 1 kg ha⁻¹ P with CPs of 10 to 50. Yield was not increased with K application. Profitability was greater for N than P application. Mean aboveground biomass N with 0 and 150 kg ha⁻¹ N applied was 46.3 and 94.3 kg ha⁻¹, respectively. Mean N concentration and N harvest index at the EONR were 1.60 and 63.8%, respectively, and higher than for N₀. Mean recovery efficiency, partial factor productivity, and agronomic efficiency declined with increasing N rate and were 66%, 86 kg kg⁻¹, and 41 kg kg⁻¹, respectively, at the EONR. Fertilizer N use can be very profitable, with high NUE, for smallholder maize production in Uganda, and the financial capacity of smallholders to use fertilizer will increase with reduced CP.