Ipilimumab is an anti-CTLA4 monoclonal antibody with demonstrated efficacy for metastatic melanoma in randomized controlled trials, including in the first-line setting. Population-based outcomes directly compared with historic chemotherapy treatment in metastatic or unresectable melanoma are lacking. Using population-based data from the province of Ontario, the benefit of first-line ipilimumab was estimated by comparing outcomes of patients treated with first-line dacarbazine over the period 2007-2009 with patients treated over the period 2010-2015 with first-line ipilimumab. Cutaneous and noncutaneous cases were included. The administrative data set utilized was high-dimensional; meaning, there was a large number of variables relative to the sample size. To adjust for important confounders among the many available variables, we utilized a double-selection method, a modified machine learning algorithm to extract the important variables that were related to both survival times and treatment usage. Time-dependent treatment modeling was utilized. Among the 2793 melanoma patients receiving palliative treatment (systemic therapy, surgery, or radiation) in Ontario (2007-2015), there were 289 patients treated with first-line ipilimumab (2010-2015) and 175 patients treated with first-line dacarbazine (2007-2009). For first-line ipilimumab, the adjusted hazard ratio compared with dacarbazine for overall survival (OS) was 0.63 (95% confidence interval: 0.47-0.84) with a 1-year survival of 46.5 versus 18.9% with dacarbazine. In subgroup analysis, ipilimumab was associated with improved OS across groups (age, sex, comorbidity, income quintile, previous interferon). First-line ipilimumab was found to have a significant OS benefit compared with historical controls in a population including those patients not routinely included in clinical trials. The treatment effect was similar to randomized controlled trials, suggesting a meaningful benefit when utilized in a population-based setting.