Tocilizumab was well tolerated, with no serious adverse events or withdrawals.<h4>Conclusions and relevance</h4>These findings highlight treatment-sensitive outcomes, effect sizes, and patient selection methods for testing systemic IL-6 inhibition in patients with difficult-to-treat depression, and call for a large-scale efficacy trial of anti-IL-6 treatment in depression.<h4>Trial registration</h4>isrctn.org Identifier: ISRCTN16942542. This evidence concerns the gene IL6 and depressive symptom measurement.