We investigated the cross-sectional relationships between thalamic lesions (i.e. total thalamic lesion volume), thalamic volume, and cognitive deficit in 55 subjects with secondary progressive multiple sclerosis. We measured: total intracranial volume, T2 lesion volume (T2LV), thalamic volume, thalamic lesions, and symbol digit modalities test (SDMT). Thalamic lesions inversely correlated with thalamic volume and these two variables were independently associated with cognitive deficit as measured by SDMT. After adjusting for T2LV, thalamic volume was the strongest predictor of cognitive deficit. Thalamic lesions may have clinical relevance independent of thalamic volume and will be longitudinally investigated in a bigger sample size.