Ruscello, B, Tozzo, N, Briotti, G, Padua, E, Ponzetti, F, and D’Ottavio, S. Influence of the number of trials and the exercise to rest ratio in repeated sprint ability, with changes of direction and orientation. J Strength Cond Res 27(7): 1904–1919, 2013—The purpose of this investigation was to determine if there were different trends in physical fatigue observed in 3 different sets, of 7 trials each, in repeated sprint training, performed in 3 different modes: straight sprinting over 30 m, shuttle sprinting over 15 + 15 m, and sprinting over 30 m with changes of direction. Recovery time among trials in the sets was administered according to the 1:5 exercise to rest ratio. The sets were performed on 3 different days, with at least 48 hours between each set. The study involved 17 trained male soccer players (height, 177.33 ± 6.21 cm; body mass, 71.63 ± 9.58 kg; body mass index, 23 ± 2.39 kg·m−2; age, 21.94 ± 3.58 years). To compare the different values of the time recorded, an index of fatigue was used. Significant differences among trials within each set (repeated measures analysis of variance; p < 0.05) and between the sets (factorial analysis of variance; p < 0.001) were found. Significant correlations between each test and countermovement jump and stiffness values recorded pre exercise were found (p < 0.05). Significant differences between countermovement jump and stiffness values recorded pre and post exercise were also found (p < 0.05). This study suggests that training sessions aimed at increasing the capacity of repeated sprint ability in nonlinear and multidirectional sprints (shuttle and change of direction), which might imply a different number of trials within the set or different exercise to rest ratios from the ones usually adopted for straight sprinting, to induce similar trends of fatigue. As practical applications, the estimated numbers of necessary trials in the different sets and the possible exercise to rest ratios, resulting from mathematical modeling, are provided for each investigated sprinting mode.