Background/Objectives: The first reimbursed prescription for palbociclib (Palbo) in breast cancer patients in Romania was issued in July 2018. The objective of this study is to assess the efficacy, safety, and adherence to Palbo in combination with aromatase inhibitor (AI) or fulvestrant in a real-world cohort of HR+/HER2− breast cancer patients from Romania. Methods: A retrospective analysis of reimbursed Palbo prescriptions was conducted using data extracted from the electronic database of the Romanian Health Insurance House, Dolj County, for disease code 124 (breast cancer), covering the period from 2018 to 2023. The primary outcome assessed was time to treatment discontinuation (TTD), with secondary outcomes including overall survival (OS) and Palbo adherence (which was measured by medication possession ratio). Results: A total of 125 patients were identified, with a median age of 62 years (IQR, 53–70), and 98% were female. Two treatment combinations were observed: Palbo + Aromatase Inhibitor (AI) in 104 patients (83.2%) and Palbo + fulvestrant in 21 patients (16.8%). The median TTD for the entire cohort was 19 months (95%CI, 19.3–24.9 months). In patients treated with Palbo + AI, the median TTD was not available/reached [NA] (95%CI, 36.0-NA months). For those receiving Palbo+fulvestrant, the median TTD was 25.0 months (95%CI, 13.0-NR months). No significant differences in TTD were observed among the two treatment combinations (χ2 = 1.33, df = 1, log-rank p = 0.249). The 12- and 36-month TTD rates were higher for Palbl combined with AI than combined with fulvestrant: 77.8% [95%CI, 69.7–86.7%] vs. 71.8% [95%CI, 53.6–96.2%], and 56.3% [95%CI, 45.9–69%] vs. 49.7% [95%CI, 29.7–83.2%], respectively. The median OS was 38 months (95%CI, 25.5–50.9). When treatment involved Palbo + AI, the median OS was NA (95%CI, 54.8-NA) months. When treatment involved Palbo + fulvestrant, the median was 50.8 (95%CI, 34.1-NA) months. Related to OS, no significant differences were found between the two types of treatments (log-rank p = 0.638). The 24- and 36-month OS rates were higher for Palbo combined with AI than combined with fulvestrant: 76.9% [95%CI, 69.2–85.5%] vs. 81% [95%CI, 65.8–99.6%], and 67.9% [95%CI, 59.2–77.8%] vs. 65.3% [95%CI, 47.4–90.0%], respectively. The mean adherence in our study was 0.91 ± 0.1. We found no correlation between adherence to Palbo and OS (Spearman’s rho = 0.04, p = 0.593). Conclusions: While both AI and fulvestrant remain viable options, the lack of significant differences in survival between these combinations suggests that treatment choice can be tailored to individual patient needs.