Vemurafenib, a B rapidly accelerated fibrosarcoma inhibitor, is commonly used in combination of cobimetinib for the treatment of melanoma. In the current study, we evaluated the relationship between vemurafenib exposure, as measured by the estimated apparent clearance (CLB) at steady state and any grade ≥3 toxicity, grade ≥3 skin rash, or toxicity requiring dose modification using pooled data from 3 prospective clinical trials involving 898 patients. A total of 69% had any grade ≥3 toxicity; grade ≥3 skin rash in 15% and 47% had a dose reduction/interruption or cessation. The median vemurafenib CLB was 1.35 L/h (interquartile range, 1.15-1.65 L/h). Lower vemurafenib CLB was significantly associated with an increased risk of grade ≥3 toxicity (hazard ratio [HR], 0.62; P <.001), grade ≥3 rash (HR, 0.29; P <.001), and adverse events requiring vemurafenib dose reduction/interruption or cessation (HR, 0.5; P <.001). When the patients were divided into 3 groups based on the vemurafenib CLB thresholds, those with low CLB (<1.22 L/h) had significantly increased incidence of any grade ≥3 toxicity or skin rash or dose adjustment, interruption, or cessation at 12 months and at day 28 when compared to those with medium (≥1.22 and <1.55 L/h) or high (>1.55 L/h) vemurafenib CLB. In conclusion, the estimated CLB of vemurafenib is associated with severe toxicities and dose adjustment or cessation, suggesting that an early estimation of vemurafenib exposure may be useful in identifying patients at risk of experiencing toxicity.