Non-compliance for immunosuppressive medication is frequent in renal transplant recipients, and associated with late acute rejection and graft loss. Although numerous studies were published on risk factors and outcome, no data are available on the histopathology of the 'non-compliant' allograft. As non-compliant patients swing between subtherapeutic and toxic doses of immunosuppression, trough levels show large variation. We questioned whether the histology of acute rejection in non-compliers (i) differs from the 'classical' acute rejection; (ii) shows more concomitant calcineurin-inhibitor toxicity; (iii) is associated with C4d and plasma cell (PC)-rich infiltrates. Based on validated interview methods/self reporting, 145 adult renal allograft recipients, transplanted for greater than one yr, on cyclosporine A and corticosteroids, were categorized as either compliant or non-compliant. Non-compliance was defined in 32 patients (22.1%). All late (greater than one yr) allograft biopsies were reviewed (Banff) and immuno-stained for C4d. Computerized morphometry was performed on late biopsies with features of acute cellular rejection. Sixty-two patients had > or =1 late biopsy [41 (36.2%) compliant/21 (65.6%) non-compliant; p = 0.0043], comprising a pool of 90 biopsies (61 compliant/29 non-compliant; p = 0.0303). 'Non-compliant' biopsies had higher scores of C4d (p = 0.0092), acute tubular damage (p = 0.0058), and peritubular capillaritis (p = 0.0070). 'Non-compliant' biopsies with acute cellular rejection showed less interstitial edema (p = 0.0165), more interstitial infiltrate (p = 0.0100), more interstitial fibrosis (p = 0.0277), and more tubular atrophy (p = 0.0197). PC-rich infiltrates correlated with C4d (p = 0.0080). Detection of non-compliance is mandatory as it represents an important cause of graft loss. This study describes histologic features of renal allograft biopsies in non-compliant patients that could help identifying this patient profile.