Purpose: Knowledge of the underlying mechanisms behind progression of chronic pancreatitis (CP) is needed to identify targets for new mechanism-based treatments. There is an urgent need for imaging biomarkers that can detect early morphological and functional pancreatic damage in order to initiate intervention and reduce the progression of CP at an early stage. The aim of our study was to assess and explore the potential role of structural magnetic resonance imaging (MRI) biomarkers for characterisation of disease progression in a CP patient cohort over a 4-year period. Methods: This longitudinal MRI study included twenty-five patients with definitive CP. Assessments of morphological imaging parameters at baseline and after 4 years included pancreatic gland volume, apparent diffusion coefficient (ADC) values, fat signal fraction (FSF) and main pancreatic duct (MPD) diameter. Patients were classified according to the modified Cambridge classification. Results: CP patients developed significantly reduced pancreatic gland volume, which decreased from mean 50.3 ± 19.6 ml at baseline to 43.5 ± 20.8 ml at follow-up (P < 0.001), decreased ADC values, meaning a higher degree of fibrosis (P < 0.001), increased FSF, meaning more fat infiltration (P < 0.001) and higher Cambridge classification scores (P = 0.033). The MPD diameter in the pancreatic head, body and tail did not change significantly over time (all P > 0.05). Only few, but no clear and systematic, associations were found between the progressions of the individual MRI measures. Conclusions: Morphological progression in patients with established CP seems to be primarily parenchymal-related. The different parenchymal changes were mostly unrelated and probably reflect diverse pathophysiological processes.