Different causes of mortality have been described over different decades followed by description of pathogens identified from infective episodes that led to death. A retrospective review was performed in 3,831 hospitalized systemic lupus erythematosus (SLE) patients in Peking Union Medical College Hospital from January 1986 to April 2012. The primary causes of death were identified, and the constituent ratio of specific death causes during different periods was compared. Among 3,831 hospitalized SLE patients, 268 patients died, accounting for 7.0 %. No significant difference of death rate was found between men and women, P = 0.404. The three most frequent death causes according to decade were as follows: for 1986-1995, renal involvement, lupus encephalopathy, and infections; for 1996-2005, infections, lupus encephalopathy, and renal involvement; and for 2006-2012, infections, lupus encephalopathy, and pulmonary hypertension. Certain types of deaths, primarily related to lupus activity, have decreased over time, whereas infections, often attributed to the use of corticosteroid and immunosuppressant medications, have increased gradually and changed to the most frequent death causes of SLE. Early mortality (<3 years) occurred more commonly in lupus encephalopathy, while late death (>3 years) happened more frequently in renal involvement, pulmonary artery hypertension, cardiovascular events, and cancer. In SLE death cases mainly dying from infection, mixed infections were more frequent than single pathogen infection (60.5 vs. 39.5 %), including common bacteria, fungal infection, and cytomegalovirus. Aspergillus fumigatus and Pneumocystis carinii were the two most commonly infected pathogens, and Cytomegalovirus was a frequent pathogen of mixed infection. Aggressive therapy has effectively reduced the mortality related to disease activity but also was associated with life-threatening infections. Mixed and fungal infection should be considered when SLE patients have severe infection.