Background: As a stand-alone intervention, saffron has efficacy for the treatment of mild-to-moderate depression. However, research as an adjunct agent is limited. Aims: The effects of saffron as an adjunct to pharmaceutical antidepressants in adults with persistent depression was investigated. Methods: In this eight-week, randomised, double-blind, placebo-controlled study, adults with persistent depression, currently taking a pharmaceutical antidepressant were given a placebo or a saffron extract (affron®, 14 mg b.i.d.). Primary outcome measures included the clinician-rated Montgomery–Åsberg Depression Rating Scale (MADRS) and self-rated MADRS (MADRS-S). Secondary outcome measures included the Antidepressant Side-Effect Checklist (ASEC) and Short Form-36 Health Survey (SF-36). Results: Of the 160 participants enrolled, 139 provided usable data. Based on the MADRS, depressive symptoms decreased more in participants taking saffron compared with a placebo, with reductions of 41 and 21%, respectively (p = 0.001). However, scores on the MADRS-S decreased 27 and 26% in the saffron and placebo conditions, respectively (p = 0.831). Saffron was associated with a greater reduction in adverse effects of antidepressants (p = 0.019), although this was non-significant after covarying for baseline values (p = 0.449). Quality of life improved in both groups with no significant between-group differences (p = 0.638). Conclusion: Adjunctive administration of a standardised saffron extract (affron®) for eight weeks was associated with a greater improvement in depressive symptoms as measured by the clinician-rated MADRS but not the self-report MADRS-S. Given the conflicting results, further research is needed to clarify the clinical benefits of saffron as an adjunctive treatment for adults with persistent depressive symptoms despite antidepressant drug treatment.