Background: All three currently approved cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) such as palbociclib, abemaciclib, and ribociclib are reported to cause significant pulmonary toxicities including fatal pneumonitis or interstitial lung disease (ILD). We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) to determine the relative risk of pneumonitis or ILD associated with CDK4/6i. Methods: We conducted a systematic search using PRISMA guidelines in PubMed, EMBASE, American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meeting abstracts from inception through Jan 30, 2021. Phase 3 RCTs using CDK4/6i in the intervention arm and reporting the number of events for pneumonitis or ILD were included in the analysis. The Cochran-Mantel-Haenszel method and random effects model were used to calculate the pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested by Cochran’s Q test and I² value. Results: Five phase 3 RCTs — MONALEESA-3, MONALEESA-7, MONARCH plus, monarchE, and PALLAS — reported the number of events for any grade pneumonitis or ILD and were included in the final analysis. A total of 13,191 patients — 6,758 in the CDK4/6i arm and 6,433 in the control arm — were analyzed. Following regimens were used in CDK4/6i arms — MONALEESA-3: ribociclib + fulvestrant; MONALEESA-7: ribociclib + tamoxifen or a non-steroidal aromatase inhibitor + goserelin; MONARCH plus: in cohort A, abemaciclib + anastrozole or letrozole, and in cohort B, abemaciclib + fulvestrant; MonarchE: abemaciclib + standard-of-care adjuvant endocrine therapy (ET); PALLAS: Palbociclib + ET. In the control arms, all studies used placebo and respective endocrine therapies. Any grade pneumonitis or ILD was reported in 1.64% of patients in the CDK4/6i arm versus 0.68% of patients in the control arm. The pooled RR of any grade pneumonitis or ILD was 2.26, 95% CI: 1.60-3.19, P < 0.00001, I² = 0%. Grade 3/4 pneumonitis or ILD was reported in 0.28% of patients in the CDK4/6i arm and 0.06% of patients in the control arm with pooled RR of 2.35, 95% CI: 0.37-15.08, P = 0.37, I² = 34%. One grade 5 pneumonitis was reported in the monarchE. Conclusions: Cyclin-dependent kinase 4/6 inhibitors are associated with increased risk of any grade pneumonitis or ILD. Early detection and prompt initiation of appropriate interventions are vital to reduce the morbidity and mortality associated with CDK4/6i induced pneumonitis or ILD.