Background: The practice of polypharmacy is prevalent among older adults and has been associated with mobility decline and cognitive impairment. However, its effects on gait performance in patients with cerebral small vessel disease (CSVD)—a population inherently vulnerable to gait disturbances—remain poorly understood. This study investigated the impact of polypharmacy on gait performance during single-task walking (STW) and dual-task walking (DTW) in patients with CSVD, and identified neuroimaging correlates associated with polypharmacy.

Methods: A total of 126 hospitalized individuals with CSVD were recruited. Based on the number of regularly used medications that had been in use for ≥2 weeks, patients were classified into three groups: non-polypharmacy (≤4 drugs, n = 47), polypharmacy (5–9 drugs, n = 49), or hyper-polypharmacy groups (≥10 drugs, n = 30). Gait speed and its coefficient of variation (CV) were recorded during STW and DTW. Magnetic resonance imaging was used to evaluate white-matter hyperintensities, lacunar infarcts, and cerebral microbleeds, which were integrated into a total CSVD burden score (0–3).

Results: During STW, the hyper-polypharmacy group had significantly slower gait speed (0.70 ± 0.20 m/s) compared to the non-polypharmacy and polypharmacy groups (both >0.91 m/s, p < 0.001). In DTW, gait speed decreased and CV increased across all groups, with the most pronounced impairments in the hyper-polypharmacy group (DTW speed: 0.59 ± 0.15 m/s; CV: 16.03%). Linear regression revealed that medication count was negatively associated with gait speed (STW β = –5.622, p < 0.001; DTW β = –8.484, p < 0.001) and positively with gait variability during DTW (β = 0.246, p < 0.001). The total CSVD score was independently associated with polypharmacy (p = 0.036).

Conclusion: The study confirmed a relationship between polypharmacy and locomotion in CSVD patients. Furthermore, total CSVD score—but not any single neuroimaging biomarker—is independently associated with the presence of polypharmacy.