Background: Modern running shoes are available in a wide range of heel-to-toe drops (ie, the height difference between the forward and rear parts of the inside of the shoe). While shoe drop has been shown to influence strike pattern, its effect on injury risk has never been investigated. Therefore, the reasons for such variety in this parameter are unclear. Purpose: The first aim of this study was to determine whether the drop of standard cushioned running shoes influences running injury risk. The secondary aim was to investigate whether recent running regularity modifies the relationship between shoe drop and injury risk. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: Leisure-time runners (N = 553) were observed for 6 months after having received a pair of shoes with a heel-to-toe drop of 10 mm (D10), 6 mm (D6), or 0 mm (D0). All participants reported their running activities and injuries (time-loss definition, at least 1 day) in an electronic system. Cox regression analyses were used to compare injury risk between the 3 groups based on hazard rate ratios (HRs) and their 95% CIs. A stratified analysis was conducted to evaluate the effect of shoe drop in occasional runners (<6 months of weekly practice over the previous 12 months) versus regular runners (≥6 months). Results: The overall injury risk was not different among the participants who had received the D6 (HR, 1.30; 95% CI, 0.86-1.98) or D0 (HR, 1.17; 95% CI, 0.76-1.80) versions compared with the D10 shoes. After stratification according to running regularity, low-drop shoes (D6 and D0) were found to be associated with a lower injury risk in occasional runners (HR, 0.48; 95% CI, 0.23-0.98), whereas these shoes were associated with a higher injury risk in regular runners (HR, 1.67; 95% CI, 1.07-2.62). Conclusion: Overall, injury risk was not modified by the drop of standard cushioned running shoes. However, low-drop shoes could be more hazardous for regular runners, while these shoes seem to be preferable for occasional runners to limit injury risk.