The classic proposal of intracellular K+ for extracellular H+ exchange as responsible for the hyperkalemia of diabetic ketoacidosis (DKA) has been questioned because experimentally induced organic anion acidosis fails to produce hyperkalemia. It has been suggested, instead, that the elevated serum [K+] of DKA might be the result of the compromised renal function, secondary to volume depletion, that usually accompanies DKA. However, several metabolic derangements other than volume depletion and acidosis, which are known to alter potassium metabolism, also develop in DKA. This study of 142 admissions for DKA examines the possible role of alterations in plasma pH, bicarbonate, glucose (G), osmolality, blood urea nitrogen (BUN) and plasma anion gap (AG) on the levels of [K+]p on admission. Significant (p less than 0.01) correlations of [K+]p with each of these parameters were found that could individually account for 8 to 15 percent of the observed variance in the plasma potassium levels; however, the effects of some or all of these parameters on the [K+]p could be independent and therefore physiologically additive. Since the parameters under study are themselves interrelated, having statistically significant correlations with each other, their possible independent role on [K+]p was evaluated by multiple regression analysis. Only plasma pH, glucose and AG emerged as having a definite independent effect on [K+]p, with no independent role found for bicarbonate, BUN and osmolality. The equation that best describes [K+]p on admission for DKA was: [K+]p = 25.4 - 3.02 pH + 0.001 G + 0.028 AG, (r = 0.515). These results indicate that the endogenous ketoacidemia and hyperglycemia observed in DKA, which result primarily from insulin deficit, are the main determinants of increased [K+]p. Since exogenous ketoacidemia and hyperglycemia in the otherwise normal experimental animal do not increase [K+]p, it is postulated that insulin deficit itself may be the major initiating cause of the hyperkalemia that develops in DKA. Renal dysfunction by enhancing hyperglycemia and reducing potassium excretion also contributes to hyperkalemia.