Background <p>Despite growing recognition of social determinants of health (SDH), quantitative evidence comparing healthcare costs between individuals with and without adverse SDH remains limited. This study addresses this gap by providing a comprehensive cost analysis comparing resource utilization and direct healthcare expenditures between populations with social determinants and those without social determinants.</p> Methodology <p>A prospective cohort study was conducted to evaluate costs by comparing individuals with unfavorable social determinants of health against those without such determinants. The study adopted a societal perspective, monitoring 638 participants over a 12-month period. A cost analysis was performed comparing basic resource utilization indicators and their associated direct costs between two groups: one comprising individuals with adverse social determinants of health (ySDH, <i>n</i> = 290) and another comprising those without such determinants (nSDH, <i>n</i> = 348). Resource utilization indicators examined included primary care visits by professional discipline, hospital-level diagnostic tests, specialist consultations, and pharmaceutical costs. Subgroup analyses examined heterogeneity by number of Z-codes, geographic location (urban/rural), and area-level socioeconomic index.</p> Results <p>Significant differences in direct costs were observed between groups. Participants with adverse social determinants incurred 23.3% higher primary care costs (€1,015 vs €823 per person annually, <i>p</i> = 0.001) and higher total healthcare utilization (22.86 vs 18.34 visits per person). Pharmaceutical expenditure was significantly higher (€432 vs €268 per person), with notable differences in psycholeptics (46.2% vs 33.0%, <i>p</i> &lt; 0.001), psychoanaleptics (30.1% vs 16.5%, <i>p</i> &lt; 0.001), analgesics, antacids, anti-anemia preparations, and antiepileptic. Subgroup analyses revealed substantial heterogeneity within the ySDH population. Patients with multiple Z-codes demonstrated 39.4% higher costs than those with single Z-codes (€1,217 vs € 873, <i>p</i> = 0.001, Cohen’s d = 0.42). The highest-risk subgroup consisted of urban patients with multiple Z-codes (€1,337, <i>n</i> = 22), representing 62.7% higher costs than urban patients with single Z-codes. Healthcare utilization patterns differed by professional discipline: nursing visits were significantly higher among ySDH patients (11.88 vs 9.17 visits, <i>p</i> = 0.003), while physician visits showed no significant difference (8.81 vs 8.09, <i>p</i> = 0.186). Geographic analysis revealed no overall urban-rural cost differences (€1,031 vs €1,014, <i>p</i> = 0.776), suggesting equitable primary care access across Catalonia.</p> Conclusions <p>Individuals with social determinants of health incur substantially higher healthcare costs, with greatest burden among those with multiple social vulnerabilities in urban settings. Healthcare utilization patterns highlight nursing’s critical role in identifying and addressing social needs. Healthcare systems should implement systematic screening for social determinants, proactive case management for high-risk subgroups (particularly patients with multiple Z-codes in urban areas), integration of the biopsychosocial model into primary care workflows, and partnerships with community organizations to address underlying social conditions. </p>