BACKGROUND AND PURPOSE: The development of effective preventive therapy for renal calculi in patients with secondary hyperoxaluria (2 degrees HO) relies on establishing the pattern of normal variation in urinary oxalate (uOx) and attempting to reduce it. Therefore, we evaluated uOx at baseline and at subsequent time points in stone formers with 2 degrees HO. METHODS: We reviewed the charts of 201 recurrent stone formers with 2 degrees HO (uOx >/= 40 mg/day). The 24-hour urine collections at baseline and after initiation of clinician-directed therapies were analyzed. Mixed models were constructed to analyze uOx over time for individual patients and as a group. Subgroup analyses were performed for enteric and idiopathic 2 degrees HO. Coefficients of variation were computed using the root mean square error from linear models. RESULTS: The etiology of 2 degrees HO was enteric in 17.9% and idiopathic in 82.1% of patients. Among the 943 urine collections analyzed, 196 oxalate values were derived from the enteric group and 747 from the idiopathic group. The median number of uOx values measured per person was four. The median 24-hour uOx (mg/day) was significantly higher for the enteric group than for the idiopathic group at the time of diagnosis: 64.4 (interquartile range [IQR]=48-90) vs 46.0 (IQR=38-56), P<0.001) and during follow-up (58.2 [IQR=46-86] vs 44.2 [IQR=35-53], P<0.001). Over a median follow-up of 22.5 months, 44.4% of the enteric and 61.8% of the idiopathic patients had at least one normal uOx value (P=0.06). The coefficients of variation for the enteric and idiopathic groups were 40.8% and 27.3%, respectively, with variation randomly displayed in either direction for both groups. CONCLUSIONS: Among patients with 2 degrees HO, uOx demonstrates significant random variation over time even with the incorporation of standard treatments, with enteric HO demonstrating higher values and greater variance than idiopathic HO.