Parent well-being is affected by their child’s oncology treatment regimen and associated caregiving demand. Parental caregiving demands and well-being were evaluated in 161 parents from 47 sites whose child was randomized to receive either a 4-hour (outpatient) or 24-hour (inpatient) methotrexate infusion during consolidation treatment for acute lymphoblastic leukemia. A majority of patients randomized to the 4-hour infusion (66.3%) received the infusion as an inpatient. The most frequently reported reasons for this were lack of an adequate outpatient facility (53.6%) and physician preference (25.0%). There were no differences between caregiving demand and well-being total scores by either randomized or actual infusion location with one exception: well-being scale fatigue scores were significantly greater (P=0.001) for parents whose child received the outpatient infusion. Mean total well-being scores for both the 24-hour arm (µ=42.6; SD 16.2) and the 4-hour arm (µ=40.6; SD 14.1) were elevated compared to healthy control populations. Additional research is needed to characterize impact of treatment setting on parental caregiving demand and well-being during their child’s treatment for acute lymphoblastic leukemia. Investigators examining impact of treatment location in randomized clinical trials need to control for institutional variability in outpatient care delivery resources.