The aim of this study is to evaluate the therapeutic outcomes, tolerability, and adherence to immediate-release (IR) and prolonged-release (PR) lithium formulations in patients with bipolar disorder (BD) over a 2-year follow-up. This naturalistic study included 143 BD patients who initiated IR (48%) or PR (52%) lithium treatment at the inpatient and outpatient services of the University Hospital of Pisa. During follow-up, data were collected on side effects, treatment adherence, blood lithium levels, and creatinine and thyroid stimulating hormone concentrations. Clinical efficacy and functioning were assessed using the Clinical Global Impressions for Bipolar Disorder and Functioning Assessment Short Test scales. Approximately 50% of patients completed the 2-year follow-up, with similar dropout rates between the two groups. Both groups showed significant clinical improvement with comparable efficacy. PR lithium, however, was associated with fewer side effects, particularly tremors and gastrointestinal issues, leading to better adherence. Additionally, PR lithium administration resulted in more stable blood lithium levels. Despite its limitations, including the observational design, potential confounders such as concomitant medications, and a high dropout rate, these findings suggest that PR lithium formulations provide similar clinical efficacy to IR formulations but offer superior tolerability. Therefore, PR lithium represents a favorable option for improving adherence, particularly in patients at risk of treatment discontinuation.