The relative risk of changes in metabolic parameters during treatment with atypical antipsychotics has not been fully investigated. Baseline-to-endpoint mean and anytime-categorical changes in metabolic parameters were evaluated in Lilly active comparator-controlled clinical trials. Olanzapine-treated patients gained significantly more baseline-to-endpoint weight versus risperidone- (3.3 kg [N = 713; median exposure [ME, days] = 68] versus 1.8 kg [N = 697; ME = 65], p < 0.001), ziprasidone-(2.8 kg [N = 463; ME = 168] versus -1.3 kg [N = 443; ME = 89], p < 0.001), and aripiprazole-treated patients (3.7 kg [N = 273; ME = 104] versus 0.5 kg [N = 275; ME = 187], p < 0.001). Significantly more olanzapine-treated patients gained ≥ 7% of their baseline weight versus risperidone-(30.6% [N = 713; ME = 169] versus 20.2% [N = 697; ME = 140], p < 0.001), ziprasidone-(30.0% [N = 463; ME = 147] versus 6.5% [N = 443; ME = 165], p < 0.001), and aripiprazole-treated patients (40.3% [N = 273; ME = 170] versus 16.4% [N = 275; ME = 154], p < 0.001). Olanzapine-treated patients had significantly greater baseline-to-endpoint changes in fasting triglycerides compared with ziprasidone- (0.24 mmol/L [N = 365; ME = 168] versus -0.24 mmol/L [N = 316; ME = 140], p < 0.001) and aripiprazole-treated patients (0.28 mmol/L [N = 215; ME = 195] versus -0.19 mmol/L [N = 210; ME = 194], p < 0.001). Olanzapine-treated patients had significantly greater baseline-to-endpoint changes in fasting glucose than ziprasidone-(0.25 mmol/L [N = 379; ME = 168] versus -0.04 mmol/L [N = 333; ME = 133], p = 0.016) and aripiprazole-treated patients (0.27 mmol/L [N = 227; ME = 195] versus 0.04 mmol/L [N = 220; ME = 194], p = 0.048). The study concluded that there are changes with varying frequencies and magnitude in some metabolic parameters in patients treated with olanzapine compared with other atypical antipsychotics.