BACKGROUND:The incidence of drug-resistant forms of tuberculosis (DR-TB) and the number of children treated with second-line drugs (SLDs) are increasing. However, limited amount of information is available regarding the use of SLDs in this population. METHODS:To describe the treatment of pediatric TB with SLDs and factors associated with use of SLDs in children with and without documented DR-TB, records of pediatric TB patients referred to a center in Italy from 2007 to 2018 were reviewed retrospectively. RESULTS:Of 204 children diagnosed with active TB during the study period, 42 were treated with SLDs because of confirmed or probable drug resistance (42.8%), adverse reactions to first-line drugs (7.1%), central nervous system involvement (11.9%) or unconfirmed possible drug resistance (38.1%). There were no deaths or adverse reactions to SLDs reported. Treatment was successful in 85.2% children treated with first-line drugs and 92.9% children treated with SLDs. After adjusting for calendar period, the only factor associated with DR-TB was <2 years old odds ratio (OR)5.24 for <2 years vs. 5–18 years; P = 0.008. Factors associated with treatment with SLDs were TB at 2 or more sites (OR11.30; P < 0.001), extrapulmonary TB (OR8.48; P < 0.001) or adverse reactions to first-line drugs (OR7.48; P = 0.002). No differences were noted in age or region of origin. CONCLUSIONS:A substantial proportion of TB children were treated with SLDs. The main reason for using SLDs was failure of a first-line drug regimen, suggesting possible DR-TB and underestimation of DR-TB in children. The use of SLD regimens was associated with a high success rate and good tolerability profile.