Children's overall tobacco smoke exposure (TSE) consists of both inhalation of secondhand smoke (SHS) and ingestion, dermal uptake, and inhalation of thirdhand smoke (THS) residue from dust and surfaces in their environments.Our objective was to compare the different roles of urinary cotinine as a biomarker of recent overall TSE and hand nicotine as a marker of children's contact with nicotine pollution in their environments. We explored the differential associations of these markers with sociodemographics, parental smoking, child TSE, and clinical diagnoses.Data were collected from 276 pediatric emergency department patients (Median age = 4.0 years) who lived with a cigarette smoker. Children's hand nicotine and urinary cotinine levels were determined using LC-MS/MS. Parents reported tobacco use and child TSE. Medical records were reviewed to assess discharge diagnoses.All children had detectable hand nicotine (GeoM = 89.7ng/wipe; 95 % CI = [78.9; 102.0]) and detectable urinary cotinine (GeoM = 10.4 ng/ml; 95%CI = [8.5; 12.6]). Although hand nicotine and urinary cotinine were highly correlated (r = 0.62, p < 0.001), urinary cotinine geometric means differed between racial groups and were higher for children with lower family income (p < 0.05), unlike hand nicotine. Independent of urinary cotinine, age, race, and ethnicity, children with higher hand nicotine levels were at increased risk to have discharge diagnoses of viral/other infectious illness (aOR = 7.49; 95%CI = [2.06; 27.24], p = 0.002), pulmonary illness (aOR = 6.56; 95%CI = [1.76; 24.43], p = 0.005), and bacterial infection (aOR = 5.45; 95%CI = [1.50; 19.85], p = 0.03). In contrast, urinary cotinine levels showed no associations with diagnosis independent of child hand nicotine levels and demographics.The distinct associations of hand nicotine and urinary cotinine suggest the two markers reflect different exposure profiles that contribute differentially to pediatric illness. Because THS in a child's environment directly contributes to hand nicotine, additional studies of children of smokers and nonsmokers are warranted to determine the role of hand nicotine as a marker of THS exposure and its potential role in the development of tobacco-related pediatric illnesses.