Background: There are limited real-world data (RWD) regarding the use of cyclin-dependent kinase (CDK) 4/6 inhibitors in western Balkan. The aim of our study was thus to analyze factors influencing progression-free survival (PFS) and overall survival (OS), along with the differences in adverse effects of CDK 4/6 therapy in a tertiary healthcare center in Croatia. Methods: We evaluated medical and demographic data for 163 consecutive patients with metastatic breast cancer treated with CDK4/6 inhibitors for at least one month, from October 2018, after the drug became available in Croatia. Eligible patients in our study were those patients who were treated with palbociclib, ribociclib, or abemaciclib. Results: The median PFS of CDK4/6 inhibitors treatment was 2.2 years (95% CI 1.8–3.3), with the longest ongoing treatment for 5.4 years. Treatment with CDK4/6 inhibitors in the first line was associated with a longer PFS compared to the second line or beyond (HR 0.50, 95% CI 0.3–0.9), and patients without liver metastasis exhibited longer survival compared to patients with liver metastasis (HR 0.46, 95% CI 0.2–0.8) (both p < 0.05). Regarding the choice of CDK4/6 inhibitors, ribociclib exhibited longer PFS compared to palbociclib (HR 0.49, 95% CI 0.29–0.82) (p = 0.0032), although the effect was not statistically significant when separating patients who were treated with CDK4/6 inhibitors in the first-line (HR 0.59, 95% CI 0.29–1.2), or second- or later-line therapy (0.49, 95% CI 0.15–1.55); the trend was present in both lines, however. The presence of liver metastasis (p = 0.04), initial luminal A grade (p = 0.039), and time to metastasis up to 5 years from the initial cancer (p = 0.002) were the only factors that remained statistically significant for PFS in multivariate analysis. Median OS since the diagnosis of metastatic disease was 4.5 years (95% CI 3.9–6.3), median OS since the start of CDK4/6 inhibitors treatment was 3.7 years (95% CI 3.4–4.4), while median OS from initial cancer diagnosis was 15.8 years (95% CI 13.8–18.3). There was no difference in OS based on the choice of CDK4/6 inhibitor (p = 0.44) or the adjuvant hormonal therapy (p = 0.12), although a nonsignificant trend for better OS with ribociclib was present for both regardless of whether it was in first- or second/later-line therapies (p > 0.05). In a multivariate analysis, only the presence of liver metastasis (p = 0.0003) and time to metastasis under 5 years from primary breast cancer (p = 0.03) were associated with a worse OS. Conclusion: Our study provides the RWD with the use of CDK4/6 inhibitors in the treatment of metastatic HR+/HER2− breast cancer. To our best knowledge, there are limited RWD regarding CDK 4/6 inhibitors use in western Balkan; thus, our study provides valuable data from everyday clinical practice for this region of Europe, bridging the gap between randomized clinical trials and clinical reality in western Balkan.