To determine the changes in serum C-reactive protein (CRP) levels during therapeutic hypothermia. Between January 2011 and June 2013, 133 hypoxic-ischemic encephalopathy patients being followed up in the neonatal intensive care unit of Dr. Sami Ulus Maternity and Children's Hospital are prospectively evaluated. Group 1; patients that received therapeutic hypothermia (n = 74) and group 2; patients that did not required therapeutic hypothermia (n = 59). All the patients underwent serial complete blood cell count and CRP assessments; blood cultures were obtained from all the cases at the time of admission and when CRP levels were elevated. Positive blood cultures were encountered in five cases (6.7%) in group 1 while no blood culture-proven septicemia was encountered in group 2. The CRP levels elevated gradually reaching a peak level on the 4th day and then decreased during the therapeutic hypothermia in patients with no blood culture-proven septicemia in group 1. The CRP levels showed statistically significant changes reaching a peak level on the 7th day in patients with blood culture-proven septicemia in group 2. Also, the CRP levels showed no alteration with time in group 2. Therapeutic hypothermia itself might be associated with CRP elevation rather than an actual infection.