To assess the hypothesis if tocilizumab (TCZ) is effective on disease activity, and also its effect in fatigue and other clinical and psychological disease-related factors in patients with rheumatoid arthritis (RA) treated with TCZ.A 24-week, multicenter, prospective, observational study in patients with moderate to severe RA receiving TCZ after failure or intolerance to disease-modifying antirheumatic drugs or tumor necrosis factor-alpha was conducted.Of the 122 patients included, 85 were evaluable for effectiveness (85% female, 51.9 ± 12.5 years, disease duration 8.7 ± 7.4 years). Mean change in C-reactive protein level from baseline to week 12 was -11.2 ± 4.0 (P < .001). Mean Disease Activity Index score (DAS28) decreased from 5.5 ± 1.0 at baseline to 2.7 ± 1.3 (P < .001) at week 24. Mean change in Functional Assessment of Chronic Illness Therapy score was -5.4 ± 11.2 points at week 24. Multiple regression analysis showed that the improvement in DAS28, sleep, and depression explained 56% and 47% of fatigue variance at week 12 and 24, respectively.Tocilizumab is effective in reducing disease activity and results in a clinically significant improvement in fatigue, pain, swollen joint count, morning stiffness, sleepiness, depression, and DAS28; the last 3 were specifically identified as factors explaining fatigue variance with the use of TCZ in RA patients.