Rice production needs to rise substantially without increasing inputs such as chemical fertilizers to feed the world’s growing population in a sustainable manner. In this regard, plant growth-promoting microorganisms, formulated as inoculant biofertilizers, show strong potential by improving nutrient use efficiency. However, the practical use of biofertilizers by farmers remains limited because of inconsistent results under field conditions. We hypothesized that biofertilizer performance depends on the amount and type of chemical fertilizer applied in concert with the biofertilizer and that such knowledge can improve inoculation efficacy. Farmer participatory field experiments were conducted at 20 different farms from two localities in the Vietnamese Mekong Delta over four growing seasons. On each farm, one half of a split-plot was treated with chemical fertilizer at conventional rates. The remaining area was given only 50–80 % of the usual chemical fertilizer rates but supplemented with the commercial biofertilizer BioGro containing four plant growth-promoting microorganisms. Our results demonstrate that the biofertilizer can replace between 23 and 52 % of nitrogen (N) fertilizer without loss of yield but cannot substitute for phosphorus (P) fertilizer. In addition, we found that up to 45 % of the variability in biofertilizer performance is related to the amount and timing of N, P, and K fertilizers applied to the crop. Importantly, the yield response to both biofertilizer and N fertilizer is strongly affected by the seasonal growing conditions. Overall, our findings show for the first time that farmer participatory experiments can be used to increase the efficacy of biofertilizers through manipulating chemical fertilizer inputs. This new information will accelerate the uptake of biofertilizer technology if managed correctly.