Objective Promptly establishing maintenance therapy could reduce morbidity and mortality in patients with bipolar disorder. Using a machine learning approach, we sought to evaluate whether lithium responsiveness (LR) is predictable using clinical markers. Method Our data are the largest existing sample of direct interview‐based clinical data from lithium‐treated patients (n = 1266, 34.7% responders), collected across seven sites, internationally. We trained a random forest model to classify LR—as defined by the previously validated Alda scale—against 180 clinical predictors. Results Under appropriate cross‐validation procedures, LR was predictable in the pooled sample with an area under the receiver operating characteristic curve of 0.80 (95% CI 0.78–0.82) and a Cohen kappa of 0.46 (0.4–0.51). The model demonstrated a particularly low false‐positive rate (specificity 0.91 0.88–0.92). Features related to clinical course and the absence of rapid cycling appeared consistently informative. Conclusion Clinical data can inform out‐of‐sample LR prediction to a potentially clinically relevant degree. Despite the relevance of clinical course and the absence of rapid cycling, there was substantial between‐site heterogeneity with respect to feature importance. Future work must focus on improving classification of true positives, better characterizing between‐ and within‐site heterogeneity, and further testing such models on new external datasets.