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Many drugs are responsible, through different mechanisms, for peripheral edema. Severity is highly variable ranging from slight edema of the lower limbs to anasarca pictures as in the capillary leak syndrome. Although most often non-inflammatory and bilateral, some drugs are associated with peripheral edema that is readily erythematous (e.g., pemetrexed) or unilateral (e.g., sirolimus). Thus, drug-induced peripheral edema is underrecognized and misdiagnosed, frequently leading to a prescribing cascade. Four main mechanisms are involved, namely precapillary arteriolar vasodilation (vasodilatory edema), sodium/water retention (renal edema), lymphatic insufficiency (lymphedema) and increased capillary permeability (permeability edema). The underlying mechanism has significant impact on treatment efficacy. The purpose of this review is to provide a comprehensive analysis of the main causative drugs by illustrating each pathophysiological mechanism and their management through an example of drug.