Effective and accessible interventions for indicated prevention of depression are necessary and lacking, especially for informal caregivers. Although telephone-based interventions could increase the accessibility for caregivers, randomized controlled trials are scarce, with no examination of prevention to date. Moreover, the efficacy of specific therapeutic components in preventive cognitive-behavioral programs is unknown. The main objective of this study was to evaluate the efficacy of a telephone-administered psychological preventive intervention in informal caregivers with high depressive symptoms. A total of 219 caregivers were randomized to a cognitive-behavioral conference call intervention (CBCC, n = 69), a behavioral-activation conference call intervention (BACC, n = 70), or a usual care control group (CG, n = 80). Both interventions consisted of five 90-minute group sessions. At the post-intervention, incidence of depression was lower in CBCC and BACC compared to CG (1.5% and 1.4% vs. 8.8%). Relative risk was 0.17 for the CBCC and 0.16 for the BACC, and the number-needed-to-treat was 14 in both groups. Depressive symptoms were significantly lower in BACC and BACC groups compared to CG (d = 1.16 and 1.29), with no significant differences between CBCC and BACC groups. The conference call intervention was effective in preventing depression and the behavioral-activation component (BACC) was comparable to the CBCC intervention.