Despite the apparent centrality of guilt in complicating reactions following bereavement, scientific investigation has been limited. Establishing the impact of specific components associated with guilt could enhance understanding. The aim of this study was to examine the relationships between two guilt-related manifestations, namely self-blame and regret, with grief and depression. A longitudinal investigation was conducted 4–7 months, 14 months and 2 years post-loss. Participants were bereaved spouses (30 widows; 30 widowers); their mean age was 53.05 years. Results showed that self-blame was associated with grief at the initial time-point and with its decline over time. Such associations were not found for depression. Initial levels of regret were neither associated with initial levels of grief and depression, nor were they related to the decline over time in either outcome variable. These results demonstrate the importance of examining guilt-related manifestations independently, over time, and with respect to both generic and grief-specific outcome variables. A main conclusion is that self-blame (but not regret) is a powerful determinant of grief-specific difficulties following the loss of a loved one. Implications for intervention are considered.