Background Macrophage activation syndrome (MAS) is an uncommon but serious complication of systemic lupus erythematosus (SLE). We aimed to identify factors associated with MAS among adult hospitalized SLE patients. Methods Within the Brigham and Women’s Hospital (BWH) Lupus Center Registry, we identified adult SLE patients > age 17 who had been hospitalized from 1970 to 2016, with either ferritin > 5000 ng/ml during admission or “macrophage activation syndrome” or “MAS” in discharge summary. We confirmed MAS by physician diagnosis in medical record review. We matched each hospitalized SLE patient with MAS to four SLE patients hospitalized without MAS (by SLE diagnosis date ±1 year). We employed conditional logistic regression models to identify clinical factors associated with MAS among hospitalized SLE patients. Results Among 2094 patients with confirmed SLE, we identified 23 who had a hospitalization with MAS and compared them to 92 hospitalized without MAS. Cases and controls had similar age at SLE diagnosis (29.0 vs. 30.5, p = 0.60), and hospital admission (43.0 vs. 38.3, p = 0.80), proportion female (78% vs. 84%, p = 0.55), and time between SLE diagnosis and hospitalization (1971 vs. 1732 days, p = 0.84). Arthritis (OR 0.04 (95% CI 0.004–0.35)) and hydroxychloroquine use (OR 0.18 (95% CI 0.04–0.72)) on admission were associated with decreased MAS risk. Admission Systemic Lupus Erythematosus Disease Activity Index scores (30 vs. 19, p = 0.002) and lengths of stay (16 days vs. 3 days, p < 0.0001) were much higher among cases. Death during hospitalization was 19% among cases and 3% among controls ( p = 0.03). Conclusions In this case-control study of hospitalized adult SLE patients, arthritis and hydroxychloroquine use at hospital admission were associated with decreased MAS risk. Further studies are needed to validate these factors associated with lowered MAS risk.