The treatment of cystinuria is hampered by methods used to measure urinary lithogenicity. Most cystine assays cannot reliably distinguish cystine from soluble thiol drug-cysteine complexes. We used a solid-phase assay of urinary cystine capacity in a large sample of patients with cystinuria. A known amount of solid-phase cystine is added to urine. In supersaturated urine, cystine precipitates onto added crystals, so the solid phase recovered after incubation will be greater than that added. We studied the effect of cystine-binding thiol drugs (CBTD) to solubilize cystine and determined correlates of cystine capacity in patients who were and were not taking CBTD. Increasing concentrations of D-penicillamine, tiopronin and captopril dissolved cystine in urine with similar efficacy. A general linear model in which 24 h cystine excretion was the dependent variable showed that creatinine, urea nitrogen, and sodium excretions were associated with cystine excretion (P<0.02, all three). Urine volume, pH, and cystine excretion strongly correlated with cystine capacity (P<0.001). Tiopronin had no effect on supersaturation in a cross-sectional analysis. A subset of supersaturated samples, with negative cystine capacity, occurred mainly among women not taking CBTD. For this subset, capacity differed significantly between CBTD users and non-users; use of CBTD avoided extremes of supersaturation. Female enrichment in the supersaturated group was accounted for in part by underprescription of CBTD to women. This assay of cystine capacity was reliable in the presence of CBTD. It should be useful in monitoring patients' response to dietary interventions and administration of fluid, citrate, and CBTD.