ABSTRACT Background PD is associated with disrupted connectivity to a large number of distributed brain regions. How the disease alters the functional topological organization of the brain, however, remains poorly understood. Furthermore, how levodopa modulates network topology in PD is largely unknown. The objective of this study was to use resting‐state functional MRI and graph theory to determine how small‐world architecture is altered in PD and affected by levodopa administration. Methods Twenty‐one PD patients and 20 controls underwent functional MRI scanning. PD patients were scanned off medication and 1 hour after 200 mg levodopa. Imaging data were analyzed using 226 nodes comprising 10 intrinsic brain networks. Correlation matrices were generated for each subject and converted into cost‐thresholded, binarized adjacency matrices. Cost‐integrated whole‐brain global and local efficiencies were compared across groups and tested for relationships with disease duration and severity. Results Data from 2 patients and 4 controls were excluded because of excess motion. Patients off medication showed no significant changes in global efficiency and overall local efficiency, but in a subnetwork analysis did show increased local efficiency in executive (P = 0.006) and salience (P = 0.018) networks. Levodopa significantly decreased local efficiency (P = 0.039) in patients except within the subcortical network, in which it significantly increased local efficiency (P = 0.007). Conclusions Levodopa modulates global and local efficiency measures of small‐world topology in PD, suggesting that degeneration of nigrostriatal neurons in PD may be associated with a large‐scale network reorganization and that levodopa tends to normalize the disrupted network topology in PD. © 2016 International Parkinson and Movement Disorder Society