Background: Sitting or standing during prolonged periods is related to leg swelling. It is unknown if interrupting sedentary behavior can attenuate lower leg swelling. We aimed to examine if adding sit-to-stand transitions prevents lower leg swelling as compared with uninterrupted motionless standing and sitting, using localized bioelectrical impedance raw parameters. Methods: Twenty adults participated in this crossover randomized controlled trial and acted out three conditions: (1) uninterrupted, motionless standing; (2) uninterrupted motionless sitting; (3) sit-to-stand transitions (1 min sitting followed by 1 min standing). Localized resistance (R), reactance (Xc), impedance (Z) and phase angle (PhA) were assessed at baseline, at 10 min and at 20 min for each condition. Results: For sitting and standing conditions, R and Xc values decreased after 10 and 20 min. Uninterrupted sitting resulted in the highest decrease in R (ΔSit − ΔStand = −9.5 Ω (4.0), p = 0.019; ΔSit − ΔInt = −11.6 Ω (4.0), p = 0.005). For standardized R (R/knee height), sitting was the condition with a greater decrease (ΔSit − ΔStand = −30.5 Ω/m (13.4), p = 0.025; ΔSit − ΔInt = −35.0 Ω/m (13.5), p = 0.011). Conclusions: Interrupting sedentary behavior by changing from sit to stand position during short periods may be effective at preventing leg swelling.