There are limited data on the medical severity of suicide attempts by intentional self-poisoning (ISP) associated with ingestion of differing classes of medications and meager data on specific agents. The purpose of the study was to address these gaps. This was an analysis of a consecutive series of ISP cases ages 13 to 65 treated at a U.S. university medical center (N = 671). The outcome, poisoning severity, was dichotomized as “moderate-severe” and “low” (reference) based on a standard measure. Class of medication (e.g., opiate) and specific agents ingested were the predictors of interest. Covariates were age, sex, and the ingestion of multiple classes of medications. Data were analyzed using multivariate logistic regression models. At the class level, ingestion of opiate was uniquely associated with increased risk for moderate-severe ISP at a statistically significant level, adjusted odds ratio (95% CI) = 2.97 (1.69, 5.21), p = .0002. Several specific agents were also associated with moderate-severe ISP. Along with the key role of opiate medications in unintentional overdose morbidity and mortality, opiate medications may also play an important and largely unrecognized role in medically serious suicidal behavior. Results also underscore the variability in toxicity of specific agents within drug classes.