Both an elevated homocysteine (Hcy) level and depression are risk factors for cognitive impairment in the general population, but no study has analyzed whether the coexistence of an elevated Hcy level and late-life depression (LLD) is associated with worse cognitive performance. We aimed to investigate the relationship between Hcy levels and cognitive function in individuals with LLD and whether the coexistence of an elevated Hcy level and LLD is associated with worse cognitive performance. A total of 113 LLD patients and 89 normal controls underwent a standardized clinical interview and comprehensive neuropsychological assessment battery. Plasma concentrations of Hcy were detected. Factorial analyses were performed to examine the impact of the coexistence of an elevated Hcy level and LLD on cognitive performance. Plasma Hcy levels in patients with LLD were significantly higher than that in normal controls. Only for LLD patients, Hcy level was negatively correlated with global cognition, executive function, attention, and visual space. The factorial analysis showed that there was a significant interactive effect of Hcy level (normal and elevated levels) and LLD (with and without LLD) on global cognition. In post hoc comparisons, the elderly individuals with both elevated Hcy levels and LLD tended to have the worst global cognitive function compared with those with LLD or elevated Hcy levels alone. The coexistence of an elevated Hcy level and LLD was associated with worse cognitive performance. Early intervention should be initiated to protect cognition in LLD patients with elevated Hcy levels. Copyright © 2020. Published by Elsevier B.V.