Background: To assess the efficacy and safety of bevacizumab-containing regimens in the treatment of advanced, chemotherapy-naive, non-squamous non-small cell lung cancer (NSCLC) on the basis of the two registrative trials [ECOG E4599 trial and BO17704 (AVAiL) trial]. Methods: A pooled analysis of the two trials was performed using a random effect model, and the results were summarized as number-needed-to-treat (NNT) and number-needed-to-harm (NNH). A 2-step analysis was performed. The primary analysis included only the patients treated with bevacizumab 15 mg/kg in the experimental arm, whereas the secondary analysis (with descriptive aim) included the patients treated with bevacizumab 15 mg/kg or those treated with bevacizumab 7.5 mg/kg in the experimental arm. The 1-year survival and 6-month progression-free rates were assumed as indexes of efficacy, and grade III–IV side effects were assumed as index of safety in both analyses. Results: 1,921 patients were potentially eligible for the pooled analysis and were included in the secondary analysis, whereas 1,576 patients were included in the primary analysis. A large heterogeneity was documented for both 6-month progression-free interval (I² = 88.164%, p = 0.004) and overall survival (I² = 73.541, p = 0.052). The absolute risk reduction of 1-year death and 6-month progression were 3.3% (95% CI = –6.5 to 13.2%, p = 0.507), with a NNT = 30; and 15.2% (95% CI = 0.07–29.6%, p = 0.04), with a NNT = 6 (both in favor of the bevacizumab-containing regimens), respectively. The absolute risk of treatment-related death was 2.4% (95% CI = 0.8–3.9%, p = 0.003), with a NNH = 41 against the bevacizumab-containing regimens; that of bleeding was 3.3% (95% CI = 1.6–4.9%, p < 0.001), with a NNH = 30; that of hypertension was 6.6% (95% CI = 4.6–8.6%, p < 0.001), with a NNH = 15; that of proteinuria was 2.1% (95% CI = 0.3–3.8%, p = 0.024), with a NNH = 47; that of neutropenia was 7.3% (95% CI = 3.2–11.4%, p < 0.001), with a NNH = 13; that of thrombocytopenia was 1.5% (95% CI = 0.2–2.7%, p = 0.021), with a NNH = 66. No significant differences were observed in the efficacy and the safety analysis when all the patients treated with bevacizumab 7.5 mg/kg and 15 mg/kg were included into the pooled analysis. Conclusion: Adding bevacizumab to standard chemotherapy in the treatment of advanced, chemotherapy-naive, non-squamous NSCLC seems to favor a modest improvement in the main outcomes, with a significant worsening of the safety profile. These data suggest caution in the generalized use of bevacizumab-containing regimens in the treatment of advanced, chemotherapy-naive, non-squamous NSCLC.