In 2 placebo-controlled studies of adults with attention-deficit/hyperactivity disorder (ADHD), SHP465 mixed amphetamine salts (MAS) extended-release significantly reduced ADHD-Rating Scale IV total score (ADHD-RS-IV-TS) versus placebo. The current post hoc analyses examined SHP465 MAS treatment response based on ADHD treatment history from the aforementioned studies. Data were pooled from 2 studies (a 7-week dose-optimization study [12.5-75 mg SHP465 MAS]; a 6-week fixed-dose study [25, 50, or 75 mg SHP465 MAS]) of adults (18‚Äì55 years) with ADHD. The primary efficacy outcome in both studies was ADHD-RS-IV-TS change from baseline to endpoint. Adverse event (AE) frequency was a secondary tolerability outcome. These post hoc analyses examined SHP465 MAS responses at endpoint in treatment-naive adults or adults previously treated with a stimulant (amphetamine or methylphenidate) in the pooled intent-to-treat population; AE frequency was examined in the pooled safety population. These pooled post hoc analyses were not preplanned, so all presented inferential statistics should not be interpreted as confirmatory. The least squares mean (95% CI) treatment differences (SHP465 MAS-placebo) for ADHD-RS-IV-TS change at endpoint favored SHP465 MAS in treatment-naive participants (-9.74 [-11.77, -7.70], nominal P < 0.0001) and participants with prior stimulant exposure (-11.80 [-16.10, -7.50], nominal P < 0.0001). Treatment-emergent AE frequency was greater with SHP465 MAS versus placebo regardless of treatment history (treatment-naive: 85.8% vs 63.9%; prior stimulant exposure: 76.9% vs 56.8%). These post hoc analyses indicate SHP465 MAS reduced ADHD symptoms more than placebo regardless of ADHD treatment history in adults with ADHD.