Hemodialysis (HD) catheter-related infection (CRI) and septicemia contribute to adverse outcomes. The impact of seasonality and prophylactic dialysis practices during high-risk periods remain unexplored. This multicenter study analyzed DOPPS data from 12,122 HD patients (from 442 facilities) to determine the association between seasonally related climatic variables and CRI and septicemia. Climatic variables were determined by linkage to National Climatic Data Center of National Oceanic and Atmospheric Administration data. Catheter care protocols were examined to determine if they could mitigate infection risk during high-risk seasons. Survival models were used to estimate the adjusted hazard ratio (AHR) of septicemia by season and by facility catheter dressing protocol. The overall catheter-related septicemia rate was 0.47 per 1000 catheter days. It varied by season, with an AHR for summer of 1.46 (95% CI: 1.19–1.80) compared with winter. Septicemia was associated with temperature (AHR = 1.07; 95% CI: 1.02–1.13; p < 0.001). Dressing protocols using chlorhexidine (AHR of septicemia = 0.55; 95% CI: 0.39–0.78) were associated with fewest episodes of CRI or septicemia. Higher catheter-related septicemia in summer may be due to seasonal conditions (e.g., heat, perspiration) that facilitate bacterial growth and compromise protective measures. Extra vigilance and use of chlorhexidine-based dressing protocols may provide prophylaxis against CRI and septicemia.