In this study, favorable conditions to achieve good combustion of cottonseed oil and its blends with diesel fuel in a direct injection diesel engine have been highlighted. This has been performed by analyzing fuel droplet size distribution and determining engine specific fuel consumption and thermal efficiency, combustion parameters (ignition delay, rate of heat release) and emissions (carbon monoxide (CO), nitrogen oxides (NOx) and carbon dioxide (CO2)). Results show that thermal efficiency and CO2 are almost similar for all tested fuels while the specific fuel consumption and CO emissions increase and NOx emissions decrease with increasing percentage of cottonseed oil in blends. Cylinder pressures are very close and rates of heat release are slightly different for cottonseed oil and diesel fuel. Results on droplet size analysis show that to obtain an adequate droplet size distribution, the percentage of cottonseed oil in diesel fuel should be limited to 40% by volume. Results on engine performance show that engine loads must be above 50%. These results are valid for diesel engines of conventional design, using low-pressure injection systems; they do not apply to modern high injection pressure engines.