An experimental investigation on sulfur dioxide removal in a pilot-scale spray dryer from the flue gas generated by combustion of low-sulfur (S) heavy oil is reported. A limewater slurry was sprayed through an ultrasonic two-fluid atomizer in the spray-dry chamber, and the spent sorbent was collected downstream in a pulse-jet baghouse together with fly ash. Flue gas was sampled at different points to measure the desulfurization efficiency after both the spray-dry chamber and the baghouse. Parametric tests were performed to study the effect of the following variables: gas inlet temperature, difference between gas outlet temperature and adiabatic saturation temperature, lime-to-S ratio, and average size of lime particles in the slurry. Results indicated that spray drying is an effective technology for the desulfurization of low-S fuel oil flue gas, provided operating conditions are chosen carefully. In particular, the lowest gas inlet and outlet temperatures compatible with baghouse operation should be selected, as should a sufficiently high lime-to-S ratio. The attainment of a small lime particle size in the slurry is critical for obtaining a high desulfurization efficiency. A previously presented spray-dry flue gas desulfurization model was used to simulate the pilot-scale desulfurization tests, to check the ability of the model to predict the S capture data and its usefulness as a design tool, minimizing the need for pilot-scale experimentation. Comparison between model and experimental results was fairly good for the whole range of calcium/S ratios considered.