Recent evidence suggests that the rapid-acting antidepressant ketamine has immune regulatory functions. The complement system is an important component of the innate immune response and plays a key role in synaptic plasticity. An increase in complement component 3 (C3) expression was previously found in the prefrontal cortex of individuals with depression. Given the complement system's role in depression and ketamine's potential anti-inflammatory properties, there is reason to suspect overlap between the complement system and ketamine's mechanism of action. This post-hoc study analyzed data from 39 individuals with major depressive disorder (MDD) and 25 healthy volunteers who previously participated in a randomized, double-blind trial comparing intravenous ketamine (0.5 mg/kg) to placebo. Blood was obtained at baseline, 230 min, Day 1, and Day 3. Plasma levels of C3a and C4a, two key complement proteins implicated in synaptic plasticity, were determined by ELISA. Linear mixed models were used to test baseline sex differences, whether differences varied by diagnosis, and ketamine's effects (versus placebo) on C3a and C4a levels in the MDD group only. A significant diagnosis-by-sex interaction was observed for C3a but not C4a levels. Drug effects on C3a and C4a levels did not vary over time. These results suggest that treatment strategies targeting the complement pathway may yield fruitful insights and/or advances in treatment options for MDD.