To evaluate whether doxycycline administered to dogs with unilateral cranial cruciate ligament rupture (Uni-CCLR) would decrease the risk of contralateral-CCLR (Co-CCLR). To evaluate predictors for Co-CCLR survival. To evaluate if a predisposition of Labrador Retrievers to Co-CCLR exists when compared to other breeds. In this prospective randomized controlled clinical trial, 69 client-owned dogs with Uni-CCLR were randomly assigned to a doxycycline (group-D: 7.5 mg/kg PO BID x 6 weeks) or non-doxycycline (group-ND: negative control). Medical and imaging data, time from Uni- to Co-CCLR and to follow-up were recorded. Statistics included chi-squared test, logistic regression, Kaplan-Meier survival analysis, log rank test, survival curves, and frailty model (p <0.05). This study included 32 dogs in group-D, and 37 dogs in group-ND. Median follow-up was 54.5 and 61 months, respectively. Contralateral CCLR occurred in 53.1% and 48.6% at medians of 20 and 11 months, respectively. Doxycycline did not significantly decrease the risk of Co-CCLR (p = 0.83). This risk was decreased by 14.2% with each year of age but increased with each increasing kilogram of body weight and each increasing degree of tibial plateau angle by 5.4% and 9.7%, respectively. Labrador Retrievers were not significantly predisposed (p = 0.37). At the dose regimen investigated doxycycline does not decrease the risk for Co-CCLR.