The nicotine metabolite ratio (NMR) is associated with race/ethnicity but has not been evaluated among smokers in the African region. We conducted a cross-sectional analysis of baseline data from a large randomized, controlled trial for smoking cessation among people with HIV (PWH) in South Africa. Urine samples were analyzed for the NMR and evaluated as a binary variable using a cutoff value of the fourth quartile to determine the fastest metabolizers. The median NMR was 0.31 (IQR: 0.31, 0.32; range: 0.29, 0.57); the cut-point for fast metabolizers was ≥0.3174 ng/mL. A high NMR was not associated with the number of cigarettes per day (OR = 1.10, 95% CI: 0.71, 1.70, p = 0.66) but was associated with 40% lower odds of a quit attempt in the past year (OR = 0.69; 95% CI: 0.44, 1.07, p = 0.09) and alcohol use (OR = 0.59, 95% CI: 0.32, 1.06, p = 0.07). No association was seen with marijuana or HIV clinical characteristics. As we found only minimal variability in the NMR and minimal associations with intensity of smoking, NMR may be of limited clinical value in this population, although it may inform which individuals are less likely to make a quit attempt.