Background: Patients with cancer are considered a highly vulnerable group, especially during the COVID-19 pandemic. There is limited literature describing the level of spiritual distress during the COVID pandemic and its association with the physical and psychological and distress in this population. Methods: Retrospective chart review of 1264 patients seen by the Outpatient Palliative Care Team from May 1st, 2020 to December 31st, 2020 (during COVID-19), 85% of the consults was delivered by Telemedicine. The association with ESAS-FS physical symptoms, Spiritual Pain (SP), anxiety and depression (none=0/10, the worst 10/10 were measured. Spiritual Pain was defined as “Pain deep in your Soul/Being that is not physical” (SP ≥1/10). Results: Spiritual Pain was present in 284/1264 (23%). Patients with Spiritual Pain were younger [Median years (Min-Max): 61 (21-90) vs. 62 (21-97), p=0.008], Hispanic [20% vs 16%, p<0.001], more single [15% vs. 10%, p<0.001], and divorced [13% vs. 9% p<0.001]. There was no association with gender and race. The frequency (%) and median intensity (0-10/10, 95%CI) of symptoms in patients with and without Spiritual Pain were, pain [90% vs 81%, 5 (0-10) vs 4 (0-10), p=0.691], fatigue [96% vs 90%, 6 (0-10) vs 5 (0-10), p<0.001], anxiety [90% vs 60%, 5 vs. 2 (0-10), (p<0.001], depression [87% vs 44%, 4 vs 0 (0-10), p<0.001], well-being [97% vs 81%, 5 (0-10) vs 3 (0-10), p=0.011], financial distress [78% vs 26%, 3 (0-10) vs 0 (0-10), p<0.001], total ESAS-FS distress [51 (7-113) vs 30 (0-92), p<0.001], respectively. 49% of patients with spiritual pain were evaluated by our psychological team vs. only 29% of those who did not have it (<0.001). Multivariate analysis for Spiritual Pain was financial distress (OR:1.24, p<0.001) and depression (OR:1.16, p<0.001). Conclusions: Important percentage of patients living with cancer experienced Spiritual Pain during COVID pandemic, this spiritual distress affected the expression of physical, psychological symptoms and worse well-being. An inclusive interdisciplinary team approach including spiritual care is needed. More research is warranted.