Background: Opioids prescribed for the management of chronic noncancer pain are associated with nausea, vomiting, and constipation. Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, has demonstrated robust efficacy and was well-tolerated in treating opioid-induced constipation without affecting central analgesia. Our objective was to assess changes in the frequency of treatment-emergent adverse events (TEAEs) after the first or second dose of methylnaltrexone or placebo. Methods: This post hoc analysis pooled data from two randomized, placebo-controlled clinical trials assessing methylnaltrexone for opioid-induced constipation in the outpatient setting. Patients received subcutaneous methylnaltrexone (12 mg once daily or 12 mg once every other day), oral methylnaltrexone (150, 300, or 450 mg daily), or placebo. TEAEs, opioid withdrawal symptoms, pain intensity, and rescue-free bowel movements (RFBMs) within 4 hours of the first dose (i.e., RFBM responders) were assessed. Associations between TEAE frequencies and RFBM response were also evaluated. Results: The analysis included 1263 adult patients with chronic noncancer pain. TEAE rates declined from treatment day 1 to 2 (methylnaltrexone: 16.2%-5.3%; placebo: 6.6%−5.4%). Among methylnaltrexone-treated patients, significantly greater proportions of RFBM responders versus nonresponders reported gastrointestinal TEAEs on day 1. No associations between RFBM response and the frequency of TEAEs were observed in the placebo group. No meaningful changes in opioid withdrawal symptoms or pain intensity were observed. Conclusions: Early-onset TEAEs following methylnaltrexone treatment, particularly gastrointestinal TEAEs, are at least partially due to laxation. Methylnaltrexone treatment effectively relieves opioid-induced constipation without affecting the central analgesic effects of opioids.