This treatment trial is aimed at assessing the short-term tolerability and efficacy of liquid-formulation extended-release methylphenidate (MPH-ER) for the treatment of ADHD in adults with high-functioning autism spectrum disorder (HF-ASD). Six-week open-label trial (ClinicalTrials.gov: NCT02096952) was conducted in 15 HF-ASD adults (mean age: 24.9 ± 4.6; male: 12 [80%]) suffering from moderate-severe ADHD. MPH-ER was administered based on a flexible titration schedule. Efficacy was assessed on clinician- and self-rated measures. Tolerability was assessed by documenting treatment-emergent adverse events (AEs) and other safety measures. Short-term MPH-ER treatment was associated with significant improvement in ADHD severity (Adult ADHD Investigator Symptom Report Scale [AISRS] mean change [MC]: -22.8 ± 8.8, p < 0.001; Adult ADHD Self-Report Scale [ASRS] MC: -8.2 ± 15.3, p < 0.001). Twelve (80%) participants were deemed responders, based on ≥30% reduction in AISRS score and an ADHD Clinical Global Impression-Improvement score ≤2. MPH-ER was well-tolerated (treatment-limiting AEs: 1/15; severe AEs: 1/15) at mean dose of 48.7 ± 15 mg/day. AEs were transient and experienced by 13/15 (87%) participants at mild to moderate severity. Frequently reported AEs were as typically expected (headache [53%], insomnia [33%], anxiety [33%], decreased appetite [27%]). Our findings suggest that MPH-ER is effective and well-tolerated in the treatment of ADHD in HF-ASD adults.