We examined hopelessness as a predictor of suicide ideation in depressed youth after acute medication treatment. A total of 158 depressed adolescents were administered the Children's Depression Rating Scale-Revised (CDRS-R) and Columbia Suicide Severity Rating Scale (C-SSRS) as part of a larger battery at baseline and at weekly visits across 6 weeks of acute fluoxetine treatment. The Beck Hopelessness Scale (BHS) was administered at baseline and week 6. A negative binomial regression model via a generalized estimating equation analysis of repeated measures was used to estimate suicide ideation over the 6 weeks of acute treatment from baseline measure of hopelessness. Depression severity and gender were included as covariates in the model. The negative binomial analysis was also conducted separately for the sample of males and females (in a gender-stratified analysis). Mean CDRS-R total scores were 60.30 ± 8.93 at baseline and 34.65 ± 10.41 at week 6. Mean baseline and week 6 BHS scores were 9.57 ± 5.51 and 5.59 ± 5.38, respectively. Per the C-SSRS, 43.04% and 83.54% reported having no suicide ideation at baseline and at week 6, respectively. The analyses revealed that baseline hopelessness was positively related to suicide ideation over treatment (p = .0027), independent of changes in depression severity. This significant finding persisted only for females (p = .0024). These results indicate the importance of early identification of hopelessness.