Summary Background Evaluation of the dosing flexibility and long‐term efficacy of biological agents is limited. Objectives To evaluate the long‐term efficacy and safety of ustekinumab with and without dosing adjustment in the 5‐year PHOENIX 2 study. Methods Patients were randomized to placebo or ustekinumab (45 or 90 mg) at weeks 0, 4, then every 12 weeks; patients receiving placebo crossed‐over at week 12. Dosing adjustments were permitted at/beyond week 28 for early adjusters (weeks 28 or 40 per response); late adjusters (during long‐term extension per investigator judgement); and nonadjusters (maintained randomized treatment throughout the study). Efficacy and safety were evaluated through weeks 244 and 264, respectively. Results In the overall population, 70% (849 of 1212) of ustekinumab‐treated patients completed treatment through week 244, with high proportions of patients responding to the 45‐mg and 90‐mg doses, respectively: 75% improvement in Psoriasis Area and Severity Index (PASI 75) (76·5% and 78·6%) and PASI 90 (50·0% and 55·5%). Approximately 20% of patients were early adjusters, 30% were late adjusters and 50% were nonadjusters. Approximately half of the late adjusters initiated adjustments after already achieving PASI 75. Improved response was generally observed following dosing adjustments. Through week 264, safety event rates did not increase and event rates were generally comparable between dose groups and between patients with and without dosing adjustment. Conclusions Treatment with ustekinumab for up to 5 years was safe and effective. Improved response was generally demonstrated following dosing adjustments; further investigations are required to quantify actual incremental benefits. The results also suggest that some patients may desire treatment goals beyond PASI 75. What's already known about this topic? Data regarding dosing adjustment from PHOENIX 1 are limited. Protocol‐defined dose‐interval adjustment was permitted only early in the study based on clinical response. What does this study add? PHOENIX 2 evaluated both protocol‐defined and investigator‐initiated dose and/or dose‐interval adjustment. Improved response was generally demonstrated following dosing adjustments; further investigations are required to quantify the actual incremental benefits. Some patients may desire treatment goals beyond 75% improvement in Psoriasis Area and Severity Index.