Lactic acidosis is one type of anion-gap metabolic acidosis (AGMA). It occurs when the tissue metabolism has to undergo anaerobic metabolism, which produces significant amounts of lactic acid.

Lactic acidosis occurs at the cellular level (mitochondria) when the oxygen delivery to the tissue is inadequate or the cells cannot utilize the oxygen. Many causes of lactic acidosis are recognized, the most common being a result of low oxygen delivery because of shock (septic, hypovolemic, cardiogenic, or neurogenic), severe anemia, or severe hypoxemia. It also can occur from exposure to drugs (e.g., metformin, antiretroviral therapy, acetaminophen, salicylates, cocaine, valproic acid, sulfasalazine, isoniazid [INH], 5-fluorouracil [5-FU]), toxins, and sugar alcohols (sorbitol, xylitol, fructose).

Many systemic diseases can also be complicated by lactic acidosis, including diabetes mellitus, alcoholism, pancreatitis, cancer, infections, vitamin B₁ deficiency, short-gut syndrome, malabsorption syndrome, etc. Certain rare inborn errors in metabolism (e.g., Von Gierke disease, methylmalonic aciduria, pyruvate dehydrogenase deficiency) can also be responsible for lactic acidosis.