Management of refractory pain in pediatric sickle cell disease (SCD) and oncology is reliant on opioids though high opioid dosing increases side effects and tachyphylaxis. We introduced low-dose ketamine infusion (LDKI) to our inpatient unit to determine if LDKI was tolerable. We subsequently hypothesized that LDKI would improve pain scores. We reviewed inpatients from LDKI initiation in March 2014 through October 2017, with the day before LDKI initiation compared with the day of LDKI initiation and 2 subsequent days. For patients with SCD, the LDKI admission was compared with up to 3 admissions in the prior year for a vaso-occlusive event. Nineteen patients (12 oncology, 7 SCD) with a median age of 14.6 years received LDKI for a median of 6 days at a median initial dose of 0.06 mg/kg/h (1.1 µg/kg/min). There was no change in pain scores or opioid utilization when comparing the day before LDKI initiation with subsequent days. No patient discontinued LDKI because of intolerability. For patients with SCD, there was a median 32% reduction in cumulative pain scores when comparing the LDKI admission with prior admissions. LDKI is well tolerated for refractory pediatric cancer-related and sickle cell-related pain.