Lipoprotein(a) (Lp(a)) is a highly atherogenic circulating lipoprotein, which, unlike the commonly studied low density lipoprotein (LDL), is entirely genetically determined with no current treatments to lower circulating levels. Hindering development of treatments, no receptors mediating Lp(a) clearance from circulation by endocytosis have been identified, and once endocytosed, the cellular catabolism of Lp(a) is unknown. Here, we sought to determine the endocytic pathway responsible for Lp(a) uptake. Our previous results indicated that Lp(a) endocytosis was calcium dependent, leading us to hypothesise that the cellular engulfment mechanism of macropinocytosis was responsible for Lp(a) uptake into the cell. Consistent with this, Lp(a) uptake was inhibited by common macropinocytosis inhibitors. In attempting to pharmacologically define Lp(a) uptake, we used the tricyclic antidepressant, imipramine, which has been recently published as a macropinocytosis inhibitor. Surprisingly, imipramine increased Lp(a) uptake, leading us to investigate whether common SSRI antidepressants modulated this process. Citalopram also robustly increased Lp(a) macropinocytosis, while fluoxetine (Prozac) and sertraline inhibited endocytosis, likely through their established inhibition of the endocytic scission protein, dynamin. As imipramine and citalopram act by increasing extracellular serotonin levels, we tested if addition of serotonin to the extracellular environment modulated Lp(a) uptake. Serotonin greatly enhanced Lp(a) uptake, but not that of the canonical macropinocytosis marker, dextran. Interestingly, serotonin specifically increased Lp(a) but not dextran binding to the cell surface, allowing increased engulfment by macropinocytosis. Together, our results indicate that Lp(a) uptake is regulated by the endocytic engulfment mechanism, macropinocytosis. Cell surface binding of Lp(a) is central for this macropinocytic uptake, and surface binding is regulated by serotonin. These results provide further evidence for the recent observation of serotonin as a fundamental regulator of endocytic processes, provide a cellular link between the clinically observed elevated Lp(a) levels and severity of depression symptoms, and indicate common antidepressants may represent effective Lp(a) lowering therapies.