Hypokalemia has been consistently reported as a common occurrence during targeted temperature management (TTM) in comatose survivors of cardiac arrest. We sought to better describe changes in serum potassium throughout the different stages of TTM and to assess for any prognostic significance. We analyzed a prospectively collected cohort of 240 patients treated with TTM following cardiac arrest at a tertiary care hospital between 2007 and 2014. The primary outcome was poor neurologic outcome at hospital discharge, defined as a Cerebral Performance Category score >2. Secondary outcomes included death and recurrent ventricular arrhythmia before hospital discharge. Multivariable logistic regression was used to assess for association of hypokalemia and hyperkalemia with the designated outcomes. During all phases of TTM, hypokalemia and hyperkalemia occurred in 207 (86%) and 77 (32%) of patients, respectively. Hypokalemia occurred in 203 (85%) patients at target temperature, and 25 (10%) patients were hyperkalemic following normothermia. In multivariable logistic regression, hypokalemia was not associated with poor neurologic outcomes or recurrent ventricular arrhythmia. Hypokalemia was associated with reduced odds of death before hospital discharge (odds ratio = 0.36, 95% confidence interval 0.13 to 0.97, p = 0.044). Hyperkalemia was not associated with poor neurologic outcomes, death, or recurrent ventricular arrhythmia.