Comorbidity burden and obesity may affect treatment response in patients with rheumatoid arthritis (RA). Few real-world studies have evaluated the impact of comorbidity burden or obesity on the effectiveness of tocilizumab (TCZ). This study evaluated TCZ effectiveness in treating RA patients with high versus low comorbidity burden and obesity versus non-obesity in US clinical practice.Patients in the Corrona RA registry who initiated TCZ were stratified by low or high comorbidity burden using a modified Charlson Comorbidity Index (mCCI) and by obese or nonobese status using body mass index (BMI). Improvements in disease activity and functionality after TCZ initiation were compared for the aforementioned strata of patients at 6 and 12 months after adjusting for statistically significant differences in baseline characteristics.We identified patients with high (mCCI ≥ 2; n = 195) and low (mCCI < 2; n = 575) comorbidity burden and patients categorized as obese (BMI ≥ 30; n = 356) and nonobese (BMI < 30; n = 449) who were treated with TCZ. Most patients (> 95%) were biologic experienced and approximately one-third of patients received TCZ as monotherapy, with no significant differences between patients by comorbidity burden or obesity status. Improvement in disease activity and functionality at 6 and 12 months was similar between groups, regardless of comorbidity burden or obesity status.In this real-world analysis, TCZ was frequently used to treat patients with high comorbidity burden or obesity. Effectiveness of TCZ did not differ by comorbidity or obesity status.