To examine clinical effectiveness, treatment complications, and healthcare costs for indigenous and non-indigenous Albertans with rheumatoid arthritis (RA) participating in the Alberta Biologics Pharmacosurveillance program. Patients initiating biologic therapy in Alberta (2004-2012) were characterized for disease severity and treatment response. Provincial hospitalization separations, physician claims, outpatient department data, and emergency department data were used to estimate treatment complication event rates and healthcare costs. Indigenous patients (n = 90) presented with higher disease activity [mean 28-joint count Disease Activity Score (DAS28) 6.11] than non-indigenous patients (n = 1400, mean DAS28 5.19, p < 0.0001). Improvements in DAS28, function, swollen joint count, CRP, and patient and physician global evaluation scores were comparable to non-indigenous patients, but indigenous patients did not have a significant improvement in erythrocyte sedimentation rate (-0.31 per month, 95% CI -0.79 to 0.16, p = 0.199). At the end of study followup, 13% (12/90) of indigenous and 33% (455/1400) of non-indigenous patients were in DAS28 remission (p < 0.001). Indigenous patients had a 40% increased risk of all-cause hospitalization [adjusted incidence rate ratio (IRR) 1.4, 95% CI 1.1-1.8, p = 0.01] and a 4-fold increase in serious infection rate (adjusted IRR 4.0, 95% CI 2.3-7.0, p < 0.001). Non-indigenous patients incurred higher costs for RA-related hospitalizations (difference $896, 95% CI 520-1273, p < 0.001), and outpatient department visits (difference $128, 95% CI 2-255, p = 0.047). We identified disparities in treatment outcomes, safety profiles, and patient-experienced effects of RA for the indigenous population in Alberta. These disparities are critical to address to facilitate and achieve desired RA outcomes from individual and population perspectives.