Follicular lymphoma (FL) is an indolent B-cell malignancy typically associated with favourable outcomes and prolonged survival. However, histological transformation (HT) occurs in a subset of patients and significantly worsens survival outcomes, markedly altering the disease course. Currently, no clinical or molecular predictors of HT are available. We sought to evaluate the potential of Serpin family E member 1 (PAI-1) as a prognostic biomarker of HT in FL, with expression levels assessed by immunohistochemistry and quantified using digital image analysis. PAI-1 expression was evaluated in diagnostic lymphoma biopsies from 30 FL patients with no record of subsequent HT with a minimum follow-up of 10 years, ranging from 10.1 to 24.8 years (non-transforming FL, nt-FL), and 18 patients with subsequent HT occurring 0.7 to 14.6 years after diagnosis (subsequently transforming FL, st-FL); furthermore, the paired high-grade biopsy from the time of HT (transformed FL, tFL) was included. No significant differential expression patterns were identified comparing nt-FL, st-FL and tFL samples. However, high intrafollicular PAI-1 expression at FL diagnosis correlated with no transformation events observed. We believe high intrafollicular PAI-1 expression at presentation might define a minor subgroup of FL patients with reduced risk of HT.