Pathogen reduction (PR) of platelet products increases costs and available clinical studies are equivocal with respect to clinical and haemostatic effectiveness. We conducted a multicentre, open-label, randomized, non-inferiority trial comparing the clinical effectiveness of buffy-coat derived leukoreduced platelet concentrates (PC) stored for up to 7 d in plasma with platelets stored in platelet additive solution III (PASIII) without and with treatment with amotosalen-HCl/ultraviolet-A (UVA) photochemical pathogen reduction (PR-PASIII). Primary endpoint of the study was 1-h corrected count increment (CCI). Secondary endpoints were 24-h CCI, bleeding, transfusion requirement of red cells and PC, platelet transfusion interval and adverse transfusion reactions. Compared to plasma-PC, in the intention to treat analysis of 278 evaluable patients the mean difference for the 1-h CCI of PR-PASIII-PC and PASIII-PC was -31% (P < 0.0001) and -9% (P = n.s.), respectively. Twenty-seven patients (32%) had bleeding events in the PR-PASIII arm, as compared to 19 (19%) in the plasma arm and 14 (15%) in the PASIII arm (P = 0.034). Despite the potential advantages of pathogen (and leucocyte) inactivation of amotosalen-HCl/UVA-treated platelet products, their clinical efficacy is inferior to platelets stored in plasma, warranting a critical reappraisal of employing this technique for clinical use.