African American (AA) males have a higher incidence and mortality rate for some cancers than other races and sexes, which could be associated with distress during treatment, medical mistrust, and health disparities. We hypothesize distress in AA males during treatment is higher than in other races and sexes. We assessed effect modification of moderate to severe (≥ 4) distress scores during cancer treatment by race and sex, age, and socioeconomic status (SES). National Comprehensive Cancer Network’s distress thermometer (scale 0–10) and characteristics for 770 cancer patients were collected from a Philadelphia hospital. Variables included age, sex, race, smoking status, marital status, SES, comorbidities, mental health, period before and during COVID-19, cancer diagnosis, and stage. Descriptive statistics, chi-square tests, and t-tests were used to compare AA and White patients. Effect modification of ≥ 4 distress by race and sex, age, and SES were analyzed by logistic regression. A p value of ≤ .05 was significant, and 95% confidence intervals (CIs) were reported. On average, AA patients had a non-significant, higher distress score (4.53, SD = 3.0) than White patients (4.22, SD = 2.9) ( p = .196). The adjusted odds ratio of ≥4 distress was 2.8 (95% CI [1.4, 5.7]) for AA males compared with White males. There was no significant difference between White and AA females, race and age, or race and SES. There was an effect modification of ≥4 distress by race and sex. AA males in cancer treatment had higher odds of ≥4 distress compared with White males.