Emerging evidence suggests schizophrenia to involve widespread alterations in the macroscale wiring architecture of the human connectome. Recent findings of attenuated connectome alterations in unaffected siblings of schizophrenia patients suggest that altered connectome organization may relate to the vulnerability to develop the disorder, but whether it relates to progression of illness after disease onset is currently unknown. Here, we examined the interaction between connectome structure and longitudinal changes in general functioning, clinical symptoms and IQ in the 3 years following MRI assessment in a group of chronically ill schizophrenia patients. Effects in patients were compared to associations between connectome organization and changes in subclinical symptoms and IQ in healthy controls and unaffected siblings of schizophrenia patients. Analyzing the patient sample revealed a relationship between structural connectivity-particularly among central 'brain hubs'-and progressive changes in general functioning (p = 0.007), suggesting that more prominent impairments of hub connectivity may herald future functional decline. Our findings further indicate that affected local connectome organization relates to longitudinal increases in overall PANSS symptoms (p = 0.013) and decreases in total IQ (p = 0.003), independent of baseline symptoms and IQ. No significant associations were observed in controls and siblings, suggesting that the findings in patients represent effects of ongoing illness, as opposed to normal time-related changes. In all, our findings suggest connectome structure to have predictive value for the course of illness in schizophrenia.