Objective To understand the side-effects of cyclophosphamide (CTX) in the treatment of systemic autoimmune diseases and the possible risk factors. Methods Two hundred and forty-one patients with systemic autoimmune diseases were recruited from the Rheumatology Division of Peking University First Hospital during January 1st, 2009 and March 31, 2012. All the patients received oral or intravenous cyclopho-sphamide. The data were collected by medical record review as well as telephone follow-up. Logistic regression analyses were used for statistical analysis. Results Statistical analysis for age, sex, disease, cumulative dose, treatment duration and mode of administration were included in the factor analysis that would impact the CTX related side-effects. Age ( x2=14.8, P=0.002), gender ( x2=11.2, P=0.001), the underlying disease ( x2=26.1, P<0.01), cumulative dose ( x2=9.8, P=0.007) and mode of administration of CTX ( x2=19.5, P<0.01) were all correlated with the incidence of CTX side-effects. Multivariate analysis showed that women [OR=2.32, 95%CI (1.15, 4.70), P=0.02], intravenous-oral sequential use of CTX [OR=5.25, 95%CI (2.30, 11.97), P<0.01] and systemic lupus erythematosus [OR=4.02, 95%CI (2.24, 7.21), P<0.01] as the underlying disease were independent risk factors for CTX side-effects. Conclusion Alopecia, gastrointestinal discomfort and gonads toxicity ware com-monly seen in Chinese patients with systemic autoimmune diseases receiving CTX. Hemor-rhagic cystitis is very rare. Women, intravenous-oral sequential use of CTX and the systemic lupus erythematosus are indepen-dent risk factors for CTX side-effects.