Background Schizophrenia is often described as a disorder of dysconnectivity, with disruptions in neural connectivity reported on the cellular microscale as well as the global macroscale level of brain organization. How these effects on these two scales are related is poorly understood. Methods First (part I of this study), we collated data on layer 3 pyramidal spine density of the healthy brain from the literature and cross-analyzed these data with new data on macroscale connectivity as derived from diffusion imaging. Second (part II of this study), we examined how alterations in regional spine density in schizophrenia are related to changes in white matter connectivity. Data on group differences in spine density were collated from histology reports in the literature and examined in a meta-regression analysis in context of alterations in macroscale white matter connectivity as derived from diffusion imaging data of a (separately acquired) group of 61 patients and 55 matched control subjects. Results Densely connected areas of the healthy human cortex were shown to overlap with areas that display high pyramidal complexity, with pyramidal neurons that are more spinous (p =.0027) compared with pyramidal neurons in areas of low macroscale connectivity. Cross-scale meta-regression analysis showed a significant association between regional variation in level of disease-related spine density reduction in schizophrenia and regional level of decrease in macroscale connectivity (two data sets examined, p =.0028 and p =.0011). Conclusions Our study presents evidence that regional disruptions in microscale neuronal connectivity in schizophrenia go hand in hand with changes in macroscale brain connectivity.