Purpose: We evaluated the clinical presentation, prevalence, and associated risk factors for focal corneal infiltrates with overlying fluorescein staining in a population of soft contact lens wearers. Methods: We measured the prevalence of focal stromal infiltrates with overlying fluorescein staining among contact lens wearers in a large cross-sectional, masked, multicenter study. Results: The practice-based occurrence of infiltrates with overlying staining was 1.6%, or 38 of 2,324 patients examined. The events were milder than those reported in studies conducted in specialty eye care centers; were usually noted during unscheduled office visits; and were accompanied by symptoms of redness, photophobia, pain, and foreign body sensation. The infiltrates were located in all corneal zones, with 44.7% of the infiltrates involving the central zone, none of which caused significant loss of acuity at follow-up. The risk factors of overnight wear, lens modality (e.g., conventional, disposable), and smoking have been confirmed. Overnight wear showed a prevalence ratio of 1.88 compared with daily wear (P<0.055, chi-square); lens modality showed an increased risk for disposables compared with conventional lenses of 2.1 (P = 0.036, chi-square). Smoking was associated with an increased prevalence of events; 1.2% of "never" and 2.2% and 2.4% of "former" and "current" smokers, respectively, experienced an infiltrate, for a prevalence ratio of 2.0 (P<0.04). Smoking and lens modality also interacted positively with extended wear, amplifying the risk associated with those factors. Conclusions: We found a 1.6% practice-based prevalence and a wide range of clinical presentation of focal infiltrates in soft contact lens wearers, and we measured the relative risks of extended wear, lens modality, and smoking in a general practice population. In these cases, there was no distinct pattern in location or severity of corneal infiltrates, and visual acuity following the events was not compromised.