This observational study aimed to identify internal (clinical-demographic, temperamental characteristics) and external (childhood trauma, psychosocial characteristics) factors potentially predicting remission at 12 weeks in bipolar-I patients experiencing manic episode and requiring to start or switch treatment with oral antipsychotics and/or mood stabilizers. The following scales were administered: the Young Mania Rating Scale (YMRS), the Montgomery-Asberg Depression Rating Scale (MADRS), the Functioning Assessment Short Test (FAST), and the Clinical Global Impression for Bipolar Disorders (CGI-BP). A logistic regression analysis was carried out to test the effect of the explored factors on remission rate (YMRS score ≤12), functionality, and clinical outcomes at week 12. Overall, 243 patients were enrolled and 197 (81.1%) completed the follow-up. Remission at week 12 was achieved in 200 (82.3%) patients. Marked improvements from baseline were observed in MADRS, FAST, CGI-BP mania, and bipolar illness scores. None of the factors was associated with remission, or showed strong correlations with the improvements in clinical health state. In our sample, after 12 weeks of initiation or change of oral therapy for mania in bipolar-I patients, treatment was associated with rapid improvements in symptoms and functioning in most patients. Factors predictive of remission and clinical improvements in manic symptoms were not identified.