Background: Protective isolation is essential for preventing infection in patients undergoing hematopoietic stem cell transplantation (HSCT). However, it is associated with significant psychosocial morbidity. Understanding the factors influencing isolation perception and its impact on care satisfaction is crucial, particularly in resource-limited settings.

Methods: This cross-sectional observational study enrolled 47 adults who underwent autologous or allogeneic HSCT at a tertiary care center in India. Perceptions of isolation and satisfaction with care were measured using validated ISOLA and FAMCARE-P16 scales, respectively. Data were analysed using correlation, multivariate regression and mediation analyses.

Results: Cluster analysis revealed that nearly half of the patients experienced a high-isolation (48.9%) and low-satisfaction (46.8%) profile. Multivariate regression identified that having a non-partner caregiver was the strongest predictor of higher perceived isolation (B = 5.62, p = 0.002). Regarding satisfaction, being unmarried was the most significant predictor of lower satisfaction (B = −24.66, p < 0.001), followed by non-Hindu religion, allogeneic transplant and poorer relationships with others. Critically, mediation analysis revealed that the effect of caregiver type on satisfaction was fully mediated by the patient’s perceived relationship with others (indirect effect: −2.71, 95% confidence intervals: −6.22 to −0.41).

Conclusion: A significant proportion of HSCT recipients experience a detrimental combination of high isolation and low satisfaction. In this exploratory study, the finding that a partner caregiver may improve satisfaction by mitigating relational alienation highlights a modifiable psychosocial target. Clinical strategies should focus on screening high-risk patients and implementing interventions to strengthen social connections for those without partners or caregivers; however, larger studies are needed to confirm these findings.