Enzalutamide (MDV3100), an androgen signaling inhibitor, has been found to improve overall survival in metastatic castration-resistant prostate cancer (mCRPC) patients with and without prior chemotherapy. We performed a meta-analysis to compare the efficacy and safety of enzalutamide between mCRPC patients who received chemotherapy and those who were chemotherapy-naïve. Both PubMed and American Society of Clinical Oncology (ASCO) conference abstracts up to June 2014 were systematically searched. Eligible studies included randomized controlled trials (RCTs) in which enzalutamide was compared to placebo in mCRPC patients with or without prior chemotherapy. Heterogeneity tests were performed to examine between-study differences in efficacy and toxicity. Summary incidences, relative risks (RR), hazard ratios (HR), and 95% confidence intervals (CI) were calculated using random- or fixed-effects models. Two phase III RCTs were included in our analysis, with one trial for patients without prior chemotherapy (N = 1,717) and another for patients after chemotherapy with docetaxel (N = 1,199). Prior chemotherapy did not alter the effect of enzalutamide on overall survival (P = 0.33) but reduced its effect on radiographic-progression free survival (P < 0.001), PSA (prostate-specific antigen)-progression free survival (P = 0.01), objective response rate (P < 0.001), and PSA response rate (P < 0.001). While prior chemotherapy was associated with a decreased risk of all-grade cardiac disorder (P = 0.02), fatigue (P < 0.001), and hypertension (P < 0.001), it was associated with an increased risk of headache (P < 0.001) attributable to enzalutamide. The effectiveness of enzalutamide may be favored in metastatic CRPC patients without prior chemotherapy. Our study’s results support enzalutamide’s suitability as a first-line treatment for mCRPC patients.