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Simple Summary: Precise and feasible prognostic scores are critical for design and enrollment of clinical trials in early-stage CLL patients at high-risk for inferior overall survival (OS). The CLL-IPI risk score is among the best validated models to predict OS in advanced-stage CLL patients receiving chemoimmunotherapy. However, data on its applicability in early-stage, Binet A, CLL patients as well as is in the modern treatment era of targeted agents are rare. Moreover, elevated beta-2-microglobulin (B2M) plasma levels account for two CLL-IPI scoring points, frequently upgrading patients to a higher risk group for inferior OS. Yet, B2M is commonly increased in patients with chronic kidney disease (CKD) per se and B2M-scoring in the CLL-IPI was not adjusted for CKD. Here we show that B2M plasma levels but not the CLL-IPI retain their prognostic value in Binet stage A CLL patients with compromised kidney function diagnosed in both treatment eras of chemoimmunotherapy and targeted agents. Background: Elevated beta-2-microglobulin (B2M) plasma levels commonly imply a higher CLL-IPI risk category for short overall survival (OS), but the risk model was not adjusted for compromised kidney function and not validated in Binet A stage CLL patients. Methods: CLL patients were identified from 2000 to 2022 at Innsbruck University Hospital, Austria. B2M levels, CLL-IPI risk stratification, and kidney function were assessed. Treatment modalities in case of disease progression and OS data during follow-up were evaluated. Results: A total of 259 Binet A stage CLL patients were identified; 16.9% (n = 44/259) presented with concurrent chronic kidney disease (CKD, GFR < 60 mL/min). Median OS was 170 months and was similar in CKD and non-CKD patients (p = 0.25). The CLL-IPI facilitated prognostic segregation in both CKD (p = 0.02) and non-CKD patients (p = 0.008). Although more frequently elevated in CKD patients (44.1% versus 10.6%, p < 0.001), B2M > 3.5 mg/L remained associated with inferior OS in this subgroup (p = 0.03). Contrary to the CLL-IPI, the prognostic value of B2M alone was also maintained in CLL patients diagnosed and potentially treated frontline in the era of targeted agents (2014–2022, p = 0.03). Conclusions: B2M retains its prognostic value for OS in early-stage CLL patients with concurrent CKD and still represents a promising covariate for up-coming prognostic models to identify patients at high risk for inferior OS in the era of targeted agents. [ABSTRACT FROM AUTHOR]