Sixty-eight field isolates of Peronophythora litchii, the causal agent of litchi downy blight, were examined for sensitivity to four novel QoI fungicides (SYP-1620, SYP-2815, ZJ0712 and enestroburin) in vitro with a mycelial growth assay. Ranges and means of EC50 values (in μg/mL) were 0.047–0.288 and 0.138 for SYP-2815, 0.056–0.992 and 0.148 for ZJ0712, 0.430–7.529 and 2.720 for SYP-1620, and 0.180–1.772 and 0.810 for enestroburin; the distributions were approximately unimodal and skewed. Eight mutants resistant to the three novel QoI fungicides and azoxystrobin (as a known QoI fungicide) were obtained by exposing field isolates to fungicide-amended agar and to ultraviolet irradiation, while mutants resistant to enestroburin were not obtained. In laboratory assays, all eight mutants had a high and stable resistance, and most were as fit or more fit than sensitive isolates. There was cross-resistance among the five QoI fungicides. The resistance risk of P. litchii to the four novel QoI fungicides was inconsistent, and the probability that P. litchii will develop resistance to SYP-2815, ZJ0712, and SYP-1620 may be high if these fungicides are frequently applied in the field.