Purpose: The present study aimed to investigate whether or not eccentric-only training induced different sex-related adaptations in vastus lateralis muscle architecture and knee extensors strength. Methods: Thirteen healthy women and 13 healthy men were recruited. Vastus lateralis pennation angle, fascicle length, and muscle thickness, as well as knee extensors eccentric, isometric, and concentric peak torque and one-repetition maximum (1RM) were measured. Both women and men underwent a unilateral iso-load knee-extension eccentric-only training with 120% of the concentric 1RM, consisting of 4 sets × 10 repetitions twice a week for a total of 8 weeks. Results: Pennation angle increased in women (+ 14%, 95% CI [10, 17], effect size [ES] = 1.54) but not in men (+ 5%, 95% CI [-1, 11], ES = 0.28), while fascicle length increased in both women (+ 7%, 95% CI [4, 10], ES = 1.02) and men (+ 12%, 95% CI [8, 16], ES = 1.82) and muscle thickness increased in women (+ 13%, 95% CI [8, 18], ES = 1.11) and men (+ 11%, 95% CI [7, 15], ES = 0.89). In both women and men, eccentric (18%, 95% CI [11, 25], ES = 0.96, and 16%, 95% CI [9, 22], ES = 0.82, respectively), isometric (17%, 95% CI [11, 23], ES = 0.53, and 17%, 95% CI [10, 24], ES = 0.62), concentric (12%, 95% CI [7, 16], ES = 0.49, and 9%, 95% CI [5, 13], ES = 0.42) peak torque and 1RM (10%, 95% CI [6, 14], ES = 0.53, and 10%, 95% CI [5, 15], ES = 0.50) similarly increased after the intervention. Conclusions: This study showed that the adaptations in strength are not sex-dependent, but the increases in pennation angle only in women suggest that the changes in muscle architecture may depend on sex.