Some patients develop persistent eye pain after refractive surgery, but the factors that cause or sustain pain are unknown. We tested whether tear proteins of patients with pain 3 months after surgery differ from patients without pain. Patients undergoing refractive surgery (LASIK or PRK) were recruited from 2 clinics and tears were collected 3 months after surgery. Participants rated their eye pain using a numerical rating scale (NRS, 0 – 10; no pain – worst pain) at baseline, 1 day, and 3 months after surgery. Using tandem mass tag (TMT) proteomic analysis, we examined tears from participants with NRS > 3 at 3 months (n=16) and a comparator group with NRS < 1 at 3 months after surgery (n=32). A subset of proteins (83 of 2748 detected, 3.0%) were associated with pain 3 months after surgery. High-dimensional statistical models showed that magnitude of differential expression was not the only important factor in classifying tear samples from pain patients. Models utilizing 3 or 4 proteins had better classification performance than single proteins and represented differences in both directions (higher or lower in pain). Thus, patterns of protein differences may serve as biomarkers of post-surgical eye pain as well as potential therapeutic targets.