The aim of this study was to assess the associations between HIV status, SARS-CoV-2 infection, increase in use of psychoactive substances and oral ulcers among people who use psychoactive substances. This was a secondary analysis of the data of 1087 people who used psychoactive substances collected during the first wave of the COVID-19 pandemic. The data extracted were confounding (age, sex, the highest level of education attained, employment status, emotional distress status), dependent (oral ulcers) and independent (SARS-CoV-2 infection, increase in alcohol consumption, smoking and use of other psychoactive substances, living with HIV) variables. A multivariate logistic regression model was constructed to determine the associations between the dependent and independent variables after adjusting for the confounding variables. Participants who had a history of SARS-CoV-2 infection (AOR:10.37) and people living with HIV (AOR:1.91) had higher odds of reporting oral ulcers. The finding suggests that people who used psychoactive substances, had COVID-19 and lived with HIV were at increased risk for oral ulcers during the first wave of the COVID-19 pandemic. Increased use of psychoactive substances was not associated with a significant increase in the risk for oral ulcers. Further research is needed to better understand the reasons for these findings.