While the incidence of psychological distress among people receiving treatment for cancer in outpatient treatment settings has received attention by researchers, few studies have investigated the incidence of psychological distress in inpatient settings. Similarly, efficacy or effectiveness studies describing psychosocial interventions with cancer patients in inpatient settings are all but absent from the research literature. The purpose of this study was to screen for psychological distress among persons receiving inpatient treatment for cancer and to then test the efficacy of a communications model known as FLEX Care (R), used to enhance routine psychosocial care, in an effort to reduce measurable levels of psychological distress. Following the vetting of more than 400 potential participants, 35 met rigorous screening criteria and also consented to participate in this randomized pre-post control group study. The intervention group received the FLEX Care (R)-enhanced routine psychosocial intervention, while the control group received the routine psychosocial intervention alone. Mean scores for psychological distress were found to be nearly twice as high in the study sample as those levels reported in outpatient studies. Additionally, participants who received the FLEX Care (R)-enhanced psychosocial intervention experienced a significant reduction in psychological distress in contrast to participants in the control setting. The findings from this study underscore the need to screen for symptoms of psychological distress in inpatient settings and lend preliminary support to the use of personalized psychosocial intervention strategies that can be used as adjuvant to routine psychosocial care in the inpatient setting to reduce psychological distress.