Background Malignant nephrosclerosis, defined as renal microangiopathy in the setting of severe hypertension, remains a critical renal emergency leading to end-stage renal disease despite aggressive anti-hypertensive treatment. Recently, activation of the complement alternative pathway (AP) has been reported to play a prominent role in the pathogenesis of malignant nephrosclerosis. However, subsequent study failed to recapitulate the findings of genetic complement abnormalities in the disease. This study aimed to determine the presence of AP activation and genetic complement defects and establish their correlations to renal microangiopathy lesions, clinical features and prognosis in patients with malignant nephrosclerosis. Methods Fifty patients with malignant hypertension and concomitant thrombotic microangiopathy (TMA) proven by renal biopsy were investigated; 25 cases of kidney donors who received zero-hour allograft biopsies were used as normal controls. Various renal TMA lesions in patients with malignant nephrosclerosis were reviewed and evaluated using a semi-quantitative scoring system. Deposition of C5b-9, C3a, C5a, C4d and mannose-binding lectin was assessed by immunohistochemistry. Co-localization of C5b-9 and CD34 was detected by confocal microscopy. Complement factor B (FB), factor P (FP; properdin), factor D (FD), factor H (FH), C3a and C5a levels were quantified by enzyme-linked immonosorbent assay in plasma and urine samples of patients with malignant nephrosclerosis and controls. Genetic abnormalities of complement components were analysed by whole-exome sequencing. Results Renal biopsies of malignant nephrosclerosis showed identical histopathological and ultrastructural features to atypical haemolytic uraemic syndrome. C5b-9, C3a and C5a deposits were found along the walls of arteries/arterioles and glomerular capillaries and localized in the endothelial cells. Elevated plasma and urinary levels of FB, FP, FD, C3a and C5a as well as decreased FH levels were observed in patients with malignant nephrosclerosis compared with normal controls. The urinary levels of complement AP components, but not the plasma levels, were correlated with renal functions, prognosis and active TMA lesions except for arteriolar thrombi. Finally, mutations of the MCP, CFB, CFH and CFHR5 genes were identified in 8 of 20 patients with malignant nephrosclerosis. Conclusions Aberrant complement AP dysregulation was demonstrated and associated with the activity, severity and renal outcomes of malignant nephrosclerosis. This observation warrants screening for complement defects in patients with malignant nephrosclerosis for the potential use of complement regulators and also highlights the need for further investigation of the precise role of AP in the pathogenesis of the disease.