Fear of cancer recurrence significantly impacts advanced cancer patients, prompting emotional distress and increased healthcare utilization. This present study aims to analyze the fear of recurrence among patients with advanced cancer undergoing systemic treatment and its relationship with sociodemographic, clinical, and psychological factors. A multicenter cross-sectional study was conducted in 15 oncology departments across Spain, involving patients with locally advanced, unresectable, or metastatic cancer eligible for systemic treatment. Participants provided demographic information and completed instruments such as the Cancer Worry Scale, Brief Symptom Inventory, Mishel Uncertainty in Illness Scale, and the Duke–UNC-11 Functional Social Support Questionnaire (DUFSSQ). A total of 1195 participants participated: median age 66, 56% male, mostly metastatic cancers (80%), and common tumor sites. Two fear groups emerged: 28% low and 72% high levels of fear. High fear was associated with being female, being younger, lower levels of education, and worse survival estimates. High fear correlated with more depression, anxiety, somatic symptoms, uncertainty, and stronger social support. Multivariate analyses indicated that younger patients, those with shorter survival estimates, higher depression and anxiety scores, more uncertainty, and stronger social support had a greater likelihood of experiencing fear of recurrence, while the opposite was true for older patients. This study underscores distinct fear of recurrence profiles in advanced cancer patients, emphasizing the need for targeted interventions and support. Future research should delve deeper into understanding their repercussions for improving patient care and well-being.