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Background Immunocompromised children might be predisposed to serious infections from human coronaviruses (HCoVs), including strains OC43, NL63, HKU1, and 229E; however, the virologic and clinical features of HCoV infection in immunocompromised children have not been compared to those in nonimmunocompromised children. Methods We retrospectively analyzed a cohort of children who presented to Seattle Children's Hospital and in whom HCoV was detected by a multiplex respiratory polymerase chain reaction assay of a nasal sample between October 2012 and March 2016. Lower respiratory tract disease (LRTD) was defined as possible or definite infiltrate seen in chest imaging, need for oxygen, or abnormal lung examination in conjunction with a physician diagnosis of LRTD. We used logistic regression modeling to evaluate risk factors for LRTD and LRTD that necessitated oxygen use (severe LRTD), including an immunocompromised state, in children with HCoV infection. Results The median ages of 85 immunocompromised and 1152 nonimmunocompromised children with HCoV infection were 6.3 and 1.6 years, respectively. The prevalence of LRTD and of severe LRTD did not differ greatly between the immunocompromised and nonimmunocompromised patients (22% vs 26% [LRTD] and 15% vs 11% [severe LRTD], respectively); however, in a multivariable model, an immunocompromised state was associated with an increased likelihood of severe LRTD (adjusted odds ratio, 2.5 [95% confidence interval, 1.2–4.9]; P =.01). Younger age, having an underlying pulmonary disorder, and the presence of respiratory syncytial virus were also associated with LRTD or severe LRTD in multivariable models. The risks of LRTD or severe LRTD did not differ among the children with different HCoV strains. Conclusions The presence of a copathogen and host factors, including an immunocompromised state, were associated with increased risk for severe LRTD. Recognizing risk factors for severe respiratory illness might assist in risk stratification. [ABSTRACT FROM AUTHOR]