Low complement is associated with clinical systemic lupus erythematosus (SLE) disease activity and future organ damage. We studied the association of hydroxychloroquine (HCQ) whole blood levels with changes in complement. We performed two analyses on data prospectively collected from an SLE cohort. In the first (a "new starts on HCQ" analysis), we compared changes in complement between those starting hydroxychloroquine and those who did not.The second analysis evaluated the association between hydroxychloroquine whole blood levels and low complement in all cohort visits using conditional logistic regression. In the "new starts on HCQ" analysis, a higher percentage of patients starting hydroxychloroquine (as reflected in HCQ blood levels>50) experienced a normalization of C4 compared to those who did not (23/57 (40%) vs. 9/56 (13%), p=0.011), as well as a significantly greater increase in both C3 and C4 (p=0.048 and p=0.017 respectively). In the "all cohort visits" analysis, there was a statistically significant higher probability of having normal C4 levels in visits with higher hydroxychloroquine whole blood levels (OR 1.8 to 2.6 depending on the levels). This relationship was most pronounced for whole blood hydroxychloroquine levels of 200ng/ml or more. We observed significant improvement in complement levels when hydroxychloroquine was started and among those with higher whole blood levels of hydroxychloroquine, particularly with respect to C4. Modulating the pathogenic mechanisms that lead to complement consumption may be one mode by which hydroxychloroquine prevents poor outcomes in SLE.