Background: Bruton’s tyrosine kinase (BTK) is essential for signaling of B-cell and chemokine receptors. Ibrutinib targets BTK and has become frontier in many hematologic malignancies. We undertook systematic review and pooled analysis of randomized controlled trials (RCTs) to determine the risk of hematologic toxicities and health-related quality of life (HRQOL) events associated with ibrutinib. Methods: We performed a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts through September 2018. Phase III RCTs that mention hematologic toxicities and HRQOL events as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio with 95% CI. Random effects model was applied. Results: 6 phase III RCTs with a total of 1,811 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle-cell lymphoma, and Waldenstrom’s macroglobulinemia were eligible. Studies compared Ibrutinib (I) vs ofatumumab, I vs chlorambucil, I+ bendamustine (B) + rituximab (R) vs placebo + B+ R, I vs temsirolimus and I vs R were included in the analysis. The relative risks (RR) of all-grade side effects were as follows: anemia, 0.812 (95% CI: 0.565–1.168; P=.261); neutropenia, 0.956 (95% CI: 0.720–1.268; P=.754); thrombocytopenia, 1.054 (95% CI: 0.450–2.470; P=.904); fatigue, 0.896 (95% CI: 0.761–1.056; P=.192); pyrexia, 1.123 (95% CI: 0.893–1.413; P=.322); and arthralgia, 1.863 (95% CI: 1.101–3.152; P=.020). The RR of high-grade adverse effects were as follows: anemia, 0.522 (95% CI: 0.371–0.733; P<.0001); neutropenia, 0.969 (95% CI: 0.751–1.249; P=.807); thrombocytopenia, 0.608 (95% CI: 0.252–1.470; P=.270); fatigue, 0.618 (95% CI: 0.396–0.964; P=.034); pyrexia, 1.165 (95% CI: 0.534–2.542; P=.701); and arthralgia, 3.623 (95% CI: 0.743–17.663; P=.111). Conclusion: Ibrutinib increased the risk of all-grade arthralgia whereas the risks of high-grade anemia and fatigue were significantly lower in the study arm, favoring ibrutinib.